Embryology - User contributions [en-gb]

2017 Group Project 5

2017-10-25T07:14:35Z

Z5178462: /* Meconium Aspiration Syndrome */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth. Although the lungs are not functional until birth, they must undergo a range of development and growth in order to function post-natally. This wiki will aim to give an overview of the anatomy and histology of the lung, the timeline of development, signalling processes that occur within the lung as well as any abnormalities that can occur during lung development.

===Lung Anatomy===

[[File:Lunganatomy.png|thumb|Lung Anatomy]]
To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is '''ciliated pseudostratified epithelium'''.

Each lung receives air through these '''primary bronchi'''. As these primary bronchi enter the lungs, they branch into smaller '''secondary bronchi''' which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains '''cilia''' and '''goblet cells'''. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. '''Bronchioles''' are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller '''terminal bronchioles'''. They are the smallest tubes in lungs and terminate at the '''alveoli'''. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===
[[File:Lung histology.png|thumb|Lung histology]]

The diagram shows the histology of the lung.

Bronchi have similar histological layers including:

* '''Mucosa''' - contains respiratory epithelium which is characterised as pseudostratified ciliated columnar epithelium with goblet cells. It also contains a lamina propria which is infiltrated with lymphocytes amidst elastic and reticular fibres.

* '''Submucosa''' - contains loose connective tissue and mixed serous and mucous glands.

* '''Muscularis''' - contains involuntary trachealis smooth muscle which allows movement of trachea and changes shape during swallowing.

* '''Adventitia''' - contains collagenous connective tissue bands and C-shaped hyaline cartilage rings.

As the bronchi branch off some changes in their histology occurs, including:

1. Cartilage rings are reduced to irregular plates of cartilage.

2. A circular band of smooth muscle develops between cartilage and mucosa.

3. Fewer goblet cells.

4. Epithelium height reduces and becomes simple columnar with fewer cilia.

Bronchioles differ in that they do not have cartilaginous plates, have an increased size of circular smooth muscle, have ciliated or non-ciliated low cuboidal epithelium and lack goblet cells.

Terminal bronchioles are the final air passageways of the conduction zone and display a reduction in the muscle layer and the lamina propria is thinner. The epithelium is also cuboidal.

The respiratory zone contains the respiratory bronchiole, alveolar ducts and sacs and alveoli.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png|thumb|Lung Cardiovasculature]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" |[[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref name="PMID28144783 "><pubmed>28144783 </pubmed></ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref name="PMID7850362"><pubmed>7850362</pubmed></ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref name="PMID5501462"><pubmed>5501462</pubmed></ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref name="PMID950075"><pubmed>950075</pubmed></ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | [[File:Pseudoglandular epithelium.gif|thumb| Epithelial structures in Pseudoglandular, Canalicular and Saccular stages of lung development <ref name="PMID28144783"/>]]

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells which preceeds the formation of the air-blood tissue barrier. <ref name="PMID20691848"><pubmed>20691848</pubmed></ref> At the end of this stage it is possible to distinguish between conducting and respiratory airways.
| width="65" | In 1971, Edward A. Boyden published an article detailing for the first time the detailed structure of a pulmonary acinus. The presence of these acini are important for the distinction between conducting and respiratory airways in the Canalicular stage.
| width="65" | [[File:Air blood barrier.gif|thumb| Change in pulmonary epithelium consequently leading to formation of the air-blood barrier in the developing lung <ref name="PMID28144783"/>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular primary septa <ref name="PMID6370120"><pubmed>6370120</pubmed></ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. Babies born prematurely that have reached this stage of lung development have a chance of surviving, directly relating to the number of lamellar bodies present.<ref> Rothstein, P. 2017. Lung Development. Columbia University. Retrieved from :http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" | In 1921, Von Neergaard discovered the function of pulmonary surfactant in newborns but the importance of his work was not recognised until the 1950s when it was rediscovered. <ref name="PMID9813256"><pubmed>9813256</pubmed></ref>The rediscovery was significant for the further understanding of Respiratory Distress Syndrome (RDS); in 1959, Avery and Mead discovered that premature infants suffering from RDS were more often surfactant deficient than not.<ref name="PMID13649082"><pubmed>13649082</pubmed></ref> This boosted research in the area of surfactant.
| width="65" | [[File:Alveolus.png|thumb|Structure of an alveolus including the structures of both Pneumocyte I and II, surfactant and lamellar body <ref name="PMID2195058"><pubmed>2195058</pubmed></ref>]]

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood. This stage involves the formation of a secondary septa and its fusing with the primary septa to produce a more effective single-layered capillary network. This is part of a process called microvascular maturation. <ref name="PMID28144783"/> In the classical mode of alveolarization, it was believed that after the formation of the new septa that alveolarizatoin ceased. However, more recent evidence has proved otherwise and shown alveolarization occurs from this stage and continues post-natally, this was termed "Continued alveolarization". The differences in these are shown in the accompanying figure. Once a child is born, massive changes occur in lung development. The alveoli formed prenatally, sometimes referred to as "primitive saccules", continue to mature and fully form up until a child is 8-10 years old. At birth, these primitive saccules number approximately 20 million and continue to develop to reach numbers of 300 million alveoli by childhood.<ref name="PMID7850362"/>
| width="65" | The Alveolarization stage of lung development has been increasingly well documented in the recent years corresponding to increasing technological advances. Traditionally, the counting of alveoli was done by assuming the structure of the alveolus and using a general equation to calculate total alveoli volume. This approach by Weibel and Gomez in 1962 set the stage for the first method of counting alveoli. <ref name="PMID14005589"><pubmed>14005589</pubmed></ref>. In 2004, Hyde et al. used a method of unbiased disector princple to estimate the Euler characteristic (a polyhedron formula) which gives an estimate of alveolar volume in the lung or in a certain section of it. An important improvement here is the implementation of an unbiased principle for the estimates made. <ref name="PMID14983516"><pubmed>14983516</pubmed></ref>
| width="65" | [[File:Alveolarization.gif|thumb| Classic and continued alveolarization in the final stage of lung development<ref name="PMID28144783"/>]]
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px|centre]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg|centre]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

===Alveolus: the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, looked at the maternal over-nutrition in the regulation of surfactant in sheep, and suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth, the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung.

One study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume with growth of the epithelial tree adapting to fill the available space in the mesenchyme.

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Mouse models have been widely used in the genetic field of research as it shares many common features with the human genome. By manipulating the gene pool, we are able to examine the physiology and anatomy of mice offsprings with selected gene characteristics. The low costs of mice, short reproductive cycle and lifespan make mice a perfect animal model to observe lung embryology. Some disadvantages that come with mice models are that they are significantly smaller than humans and have immunological differences, such as a lack of IL-8.

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: GATA6, Bmp, Wnt7b, Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
Sox 2 is a Sry related HMG in a conserved family of transcription factors, where different Sox proteins will regulate different gene targets. SOX genes have always had a major role in the modulation of fetal development and cell differentiation. In particular, Sox 2 has been seen in neurogenesis, neural stem cells and hair cells in the cochlea. For the lung specifically, Sox 2 has been suggested to have a role in branching morphogenesis and early fetal lung development. In animals lung models, overexpressed Sox 2 lead to early differentiation in cells and premature commitment. It was shown to drive precursor-like cells to a commited state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif and modulates gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium. To analyse the role of GATA6 in fetal lung development, expression patterns of lungs in early development were examined suggesting that this transcription factor is involved in branching morphogenesis. Chimeric embryos were produced from ES cells and lungs were dissected at different E days. In the chimeric lungs of mouse in earlier E days had smaller and less lung buds compared to non-chimeric lungs and had fewer branches. In defective GATA6 endoderm, the abnormal phenotype displayed was due to abnormal branching morphogenesis as a result of delayed epithelial differentiation.

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===

[[File:MAS.jpg|250px|thumb|right|Lateral view of a chest radiography of an infant with MAS.]]

Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth. Chest radiography often shows diffused bilateral fluffy densities. <ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

[[File:CPAMXCT.jpg|350px|thumb|right|Chest radiography and contrast CT imaging of the lungs of a 36-year old woman diagnosed with CPAM.]]

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

Cystic fibrosis (CF) is a disease caused an extreme functional deficiency of the cystic fibrosis trans-membrane conductance regulator (CFTR) protein. It is found in high numbers in epithelial cells that line the cylindrical structures of tissue that often secrete fluids rich in mucus, such as the pancreas and the lungs. Out of all the tissues, the airways have one of the highest amount of CFTR. With the absence of functional CFTR in the lungs, there is defective chloride and bicarbonate secretion into the alveolar secretions. This causes the pH of the airway surface fluid to drop and also prevents secretion of mucus strands from glands. This results in a condition known as CF lung disease. <ref name="PMID25814049"><pubmed>25814049</pubmed></ref>

====Cystic Fibrosis Lung Disease====

This disease is identified by early colonisation and infection of the airways. Due to the acidic conditions of the CF airway surfaces, there is often a significant flaw in the baby's anti-bacterial defences. This leads to a very rapid onset of infection and the resulting inflammatory response is very critical.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> The usual culprits are Staphylococcus aureus and Pseusdomonas aeruginosa, which when mucoid, becomes the dominant pathogen that attacks CF lung tissues.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref> The chronic airway and systemic inflammation that occurs as a result would then lead to tissue destruction and respiratory failure.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> In fact, respiratory failure secondary to lung damage is the usually cause of death for CF patients with most of the damage caused arising from the inflammation instead of the actual bacteria.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref>

==Future questions==

==Glossary==
{|
|-bgcolor="#FBA08D"
| width="150" |<center>'''Term''' </center>
| width="350" |<center>'''Definition'''</center>
|-
| '''Alveoli''' || Microscopic air sacs that inflate and allow respiratory function in the lungs; they are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs.
|- bgcolor="#F2BFB5"
| '''Bronchiole''' || Branchings that form off the bronchus in the lungs and continue to divide into alveoli
|-
| '''Bronchus''' || Two main divisions that that divide from the trachea and further into bronchioles
|-bgcolor="#F2BFB5"
| '''Cilia''' || Microscopic hair-like extensions of epithelia that provide propulsion
|-
| '''Fibroblast Growth Factor (FGF10)''' || serves as a signalling cue for epithelium outgrowth in the mesenchyme.
|-bgcolor="#F2BFB5"
| '''Gastrulation''' || A phase of the embryonic period that sees the formation of the three Germ layers
|-
| '''Germ layers''' || There are three germ layers formed at the end of gastrulation; the ectoderm (responsible for the epidermis, nervous system and neural crest), the endoderm (responsible for epithelium of the respiratory and digestive systems) and the mesoderm (responsible for connective tissues).
|-bgcolor="#F2BFB5"
| '''Goblet Cells''' || Seen microscopically in epithelia and secrete mucus to coat lining of respiratory tract
|-
| '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' || interacts with SHH in order to produce epthelial cells and lung morphogenesis
|-bgcolor="#F2BFB5"
| '''Interstitium''' || Spaces between organs or tissues; in this page, used to refer to the space between pulmonary epithelia and vascular system
|-
| '''Mesenchyme''' || Unorganised connective tissue commonly found in embryonic development, mainly comprised of ground substance
|-bgcolor="#F2BFB5"
| '''Parenchyma''' || The functional cells of an organ or tissue
|-
| '''Planar and orthogonal branching''' || Planar branching refers to branching in one plane of reference whereas orthogonal branching is branching at right angles
|-bgcolor="#F2BFB5"
| '''Septum''' || Plural form: Septa, a division between two chambers; in this page used as reference to the divisions of the respiratory lobes in early lung development
|-
| '''Sonic Hedgehog (SHH)''' || produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.
|-bgcolor="#F2BFB5"
| '''Sox9''' || promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix.
|-
| '''Tachypnoea''' || Atypical rapid breathing
|-bgcolor="#F2BFB5"
| '''Terminal broncihole''' || the final air passageways of the conduction zone; they display a reduction in the muscle layer and a thinner lamina propria
|-
| '''Type I Alveolar Cells''' || Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.
|- bgcolor="#F2BFB5"
| '''Type II Alveolar Cells''' || Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.
|-
|'''Wnt7b''' || a protein encoding Wnt7b protein, in charge of deciding cell fate and patterning during embryogenesis
|}

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-25T07:12:23Z

Z5178462: /* Meconium Aspiration Syndrome */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth. Although the lungs are not functional until birth, they must undergo a range of development and growth in order to function post-natally. This wiki will aim to give an overview of the anatomy and histology of the lung, the timeline of development, signalling processes that occur within the lung as well as any abnormalities that can occur during lung development.

===Lung Anatomy===

[[File:Lunganatomy.png|thumb|Lung Anatomy]]
To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is '''ciliated pseudostratified epithelium'''.

Each lung receives air through these '''primary bronchi'''. As these primary bronchi enter the lungs, they branch into smaller '''secondary bronchi''' which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains '''cilia''' and '''goblet cells'''. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. '''Bronchioles''' are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller '''terminal bronchioles'''. They are the smallest tubes in lungs and terminate at the '''alveoli'''. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===
[[File:Lung histology.png|thumb|Lung histology]]

The diagram shows the histology of the lung.

Bronchi have similar histological layers including:

* '''Mucosa''' - contains respiratory epithelium which is characterised as pseudostratified ciliated columnar epithelium with goblet cells. It also contains a lamina propria which is infiltrated with lymphocytes amidst elastic and reticular fibres.

* '''Submucosa''' - contains loose connective tissue and mixed serous and mucous glands.

* '''Muscularis''' - contains involuntary trachealis smooth muscle which allows movement of trachea and changes shape during swallowing.

* '''Adventitia''' - contains collagenous connective tissue bands and C-shaped hyaline cartilage rings.

As the bronchi branch off some changes in their histology occurs, including:

1. Cartilage rings are reduced to irregular plates of cartilage.

2. A circular band of smooth muscle develops between cartilage and mucosa.

3. Fewer goblet cells.

4. Epithelium height reduces and becomes simple columnar with fewer cilia.

Bronchioles differ in that they do not have cartilaginous plates, have an increased size of circular smooth muscle, have ciliated or non-ciliated low cuboidal epithelium and lack goblet cells.

Terminal bronchioles are the final air passageways of the conduction zone and display a reduction in the muscle layer and the lamina propria is thinner. The epithelium is also cuboidal.

The respiratory zone contains the respiratory bronchiole, alveolar ducts and sacs and alveoli.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png|thumb|Lung Cardiovasculature]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" |[[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref name="PMID28144783 "><pubmed>28144783 </pubmed></ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref name="PMID7850362"><pubmed>7850362</pubmed></ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref name="PMID5501462"><pubmed>5501462</pubmed></ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref name="PMID950075"><pubmed>950075</pubmed></ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | [[File:Pseudoglandular epithelium.gif|thumb| Epithelial structures in Pseudoglandular, Canalicular and Saccular stages of lung development <ref name="PMID28144783"/>]]

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells which preceeds the formation of the air-blood tissue barrier. <ref name="PMID20691848"><pubmed>20691848</pubmed></ref> At the end of this stage it is possible to distinguish between conducting and respiratory airways.
| width="65" | In 1971, Edward A. Boyden published an article detailing for the first time the detailed structure of a pulmonary acinus. The presence of these acini are important for the distinction between conducting and respiratory airways in the Canalicular stage.
| width="65" | [[File:Air blood barrier.gif|thumb| Change in pulmonary epithelium consequently leading to formation of the air-blood barrier in the developing lung <ref name="PMID28144783"/>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular primary septa <ref name="PMID6370120"><pubmed>6370120</pubmed></ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. Babies born prematurely that have reached this stage of lung development have a chance of surviving, directly relating to the number of lamellar bodies present.<ref> Rothstein, P. 2017. Lung Development. Columbia University. Retrieved from :http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" | In 1921, Von Neergaard discovered the function of pulmonary surfactant in newborns but the importance of his work was not recognised until the 1950s when it was rediscovered. <ref name="PMID9813256"><pubmed>9813256</pubmed></ref>The rediscovery was significant for the further understanding of Respiratory Distress Syndrome (RDS); in 1959, Avery and Mead discovered that premature infants suffering from RDS were more often surfactant deficient than not.<ref name="PMID13649082"><pubmed>13649082</pubmed></ref> This boosted research in the area of surfactant.
| width="65" | [[File:Alveolus.png|thumb|Structure of an alveolus including the structures of both Pneumocyte I and II, surfactant and lamellar body <ref name="PMID2195058"><pubmed>2195058</pubmed></ref>]]

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood. This stage involves the formation of a secondary septa and its fusing with the primary septa to produce a more effective single-layered capillary network. This is part of a process called microvascular maturation. <ref name="PMID28144783"/> In the classical mode of alveolarization, it was believed that after the formation of the new septa that alveolarizatoin ceased. However, more recent evidence has proved otherwise and shown alveolarization occurs from this stage and continues post-natally, this was termed "Continued alveolarization". The differences in these are shown in the accompanying figure. Once a child is born, massive changes occur in lung development. The alveoli formed prenatally, sometimes referred to as "primitive saccules", continue to mature and fully form up until a child is 8-10 years old. At birth, these primitive saccules number approximately 20 million and continue to develop to reach numbers of 300 million alveoli by childhood.<ref name="PMID7850362"/>
| width="65" | The Alveolarization stage of lung development has been increasingly well documented in the recent years corresponding to increasing technological advances. Traditionally, the counting of alveoli was done by assuming the structure of the alveolus and using a general equation to calculate total alveoli volume. This approach by Weibel and Gomez in 1962 set the stage for the first method of counting alveoli. <ref name="PMID14005589"><pubmed>14005589</pubmed></ref>. In 2004, Hyde et al. used a method of unbiased disector princple to estimate the Euler characteristic (a polyhedron formula) which gives an estimate of alveolar volume in the lung or in a certain section of it. An important improvement here is the implementation of an unbiased principle for the estimates made. <ref name="PMID14983516"><pubmed>14983516</pubmed></ref>
| width="65" | [[File:Alveolarization.gif|thumb| Classic and continued alveolarization in the final stage of lung development<ref name="PMID28144783"/>]]
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px|centre]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg|centre]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

===Alveolus: the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, looked at the maternal over-nutrition in the regulation of surfactant in sheep, and suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth, the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung.

One study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume with growth of the epithelial tree adapting to fill the available space in the mesenchyme.

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Mouse models have been widely used in the genetic field of research as it shares many common features with the human genome. By manipulating the gene pool, we are able to examine the physiology and anatomy of mice offsprings with selected gene characteristics. The low costs of mice, short reproductive cycle and lifespan make mice a perfect animal model to observe lung embryology. Some disadvantages that come with mice models are that they are significantly smaller than humans and have immunological differences, such as a lack of IL-8.

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: GATA6, Bmp, Wnt7b, Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
Sox 2 is a Sry related HMG in a conserved family of transcription factors, where different Sox proteins will regulate different gene targets. SOX genes have always had a major role in the modulation of fetal development and cell differentiation. In particular, Sox 2 has been seen in neurogenesis, neural stem cells and hair cells in the cochlea. For the lung specifically, Sox 2 has been suggested to have a role in branching morphogenesis and early fetal lung development. In animals lung models, overexpressed Sox 2 lead to early differentiation in cells and premature commitment. It was shown to drive precursor-like cells to a commited state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif and modulates gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium. To analyse the role of GATA6 in fetal lung development, expression patterns of lungs in early development were examined suggesting that this transcription factor is involved in branching morphogenesis. Chimeric embryos were produced from ES cells and lungs were dissected at different E days. In the chimeric lungs of mouse in earlier E days had smaller and less lung buds compared to non-chimeric lungs and had fewer branches. In defective GATA6 endoderm, the abnormal phenotype displayed was due to abnormal branching morphogenesis as a result of delayed epithelial differentiation.

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===

[[File:MAS.jpg|250px|thumb|right|Lateral view of a chest radiography of an infant with MAS.]]

Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth. Chest radiography often shows diffused bilateral fluffy densities as seen in the Image. <ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

[[File:CPAMXCT.jpg|350px|thumb|right|Chest radiography and contrast CT imaging of the lungs of a 36-year old woman diagnosed with CPAM.]]

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

Cystic fibrosis (CF) is a disease caused an extreme functional deficiency of the cystic fibrosis trans-membrane conductance regulator (CFTR) protein. It is found in high numbers in epithelial cells that line the cylindrical structures of tissue that often secrete fluids rich in mucus, such as the pancreas and the lungs. Out of all the tissues, the airways have one of the highest amount of CFTR. With the absence of functional CFTR in the lungs, there is defective chloride and bicarbonate secretion into the alveolar secretions. This causes the pH of the airway surface fluid to drop and also prevents secretion of mucus strands from glands. This results in a condition known as CF lung disease. <ref name="PMID25814049"><pubmed>25814049</pubmed></ref>

====Cystic Fibrosis Lung Disease====

This disease is identified by early colonisation and infection of the airways. Due to the acidic conditions of the CF airway surfaces, there is often a significant flaw in the baby's anti-bacterial defences. This leads to a very rapid onset of infection and the resulting inflammatory response is very critical.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> The usual culprits are Staphylococcus aureus and Pseusdomonas aeruginosa, which when mucoid, becomes the dominant pathogen that attacks CF lung tissues.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref> The chronic airway and systemic inflammation that occurs as a result would then lead to tissue destruction and respiratory failure.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> In fact, respiratory failure secondary to lung damage is the usually cause of death for CF patients with most of the damage caused arising from the inflammation instead of the actual bacteria.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref>

==Future questions==

==Glossary==
{|
|-bgcolor="#FBA08D"
| width="150" |<center>'''Term''' </center>
| width="350" |<center>'''Definition'''</center>
|-
| '''Alveoli''' || Microscopic air sacs that inflate and allow respiratory function in the lungs; they are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs.
|- bgcolor="#F2BFB5"
| '''Bronchiole''' || Branchings that form off the bronchus in the lungs and continue to divide into alveoli
|-
| '''Bronchus''' || Two main divisions that that divide from the trachea and further into bronchioles
|-bgcolor="#F2BFB5"
| '''Cilia''' || Microscopic hair-like extensions of epithelia that provide propulsion
|-
| '''Fibroblast Growth Factor (FGF10)''' || serves as a signalling cue for epithelium outgrowth in the mesenchyme.
|-bgcolor="#F2BFB5"
| '''Gastrulation''' || A phase of the embryonic period that sees the formation of the three Germ layers
|-
| '''Germ layers''' || There are three germ layers formed at the end of gastrulation; the ectoderm (responsible for the epidermis, nervous system and neural crest), the endoderm (responsible for epithelium of the respiratory and digestive systems) and the mesoderm (responsible for connective tissues).
|-bgcolor="#F2BFB5"
| '''Goblet Cells''' || Seen microscopically in epithelia and secrete mucus to coat lining of respiratory tract
|-
| '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' || interacts with SHH in order to produce epthelial cells and lung morphogenesis
|-bgcolor="#F2BFB5"
| '''Interstitium''' || Spaces between organs or tissues; in this page, used to refer to the space between pulmonary epithelia and vascular system
|-
| '''Mesenchyme''' || Unorganised connective tissue commonly found in embryonic development, mainly comprised of ground substance
|-bgcolor="#F2BFB5"
| '''Parenchyma''' || The functional cells of an organ or tissue
|-
| '''Planar and orthogonal branching''' || Planar branching refers to branching in one plane of reference whereas orthogonal branching is branching at right angles
|-bgcolor="#F2BFB5"
| '''Septum''' || Plural form: Septa, a division between two chambers; in this page used as reference to the divisions of the respiratory lobes in early lung development
|-
| '''Sonic Hedgehog (SHH)''' || produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.
|-bgcolor="#F2BFB5"
| '''Sox9''' || promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix.
|-
| '''Tachypnoea''' || Atypical rapid breathing
|-bgcolor="#F2BFB5"
| '''Terminal broncihole''' || the final air passageways of the conduction zone; they display a reduction in the muscle layer and a thinner lamina propria
|-
| '''Type I Alveolar Cells''' || Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.
|- bgcolor="#F2BFB5"
| '''Type II Alveolar Cells''' || Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.
|-
|'''Wnt7b''' || a protein encoding Wnt7b protein, in charge of deciding cell fate and patterning during embryogenesis
|}

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-25T07:10:23Z

Z5178462: /* Meconium Aspiration Syndrome */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth. Although the lungs are not functional until birth, they must undergo a range of development and growth in order to function post-natally. This wiki will aim to give an overview of the anatomy and histology of the lung, the timeline of development, signalling processes that occur within the lung as well as any abnormalities that can occur during lung development.

===Lung Anatomy===

[[File:Lunganatomy.png|thumb|Lung Anatomy]]
To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is '''ciliated pseudostratified epithelium'''.

Each lung receives air through these '''primary bronchi'''. As these primary bronchi enter the lungs, they branch into smaller '''secondary bronchi''' which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains '''cilia''' and '''goblet cells'''. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. '''Bronchioles''' are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller '''terminal bronchioles'''. They are the smallest tubes in lungs and terminate at the '''alveoli'''. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===
[[File:Lung histology.png|thumb|Lung histology]]

The diagram shows the histology of the lung.

Bronchi have similar histological layers including:

* '''Mucosa''' - contains respiratory epithelium which is characterised as pseudostratified ciliated columnar epithelium with goblet cells. It also contains a lamina propria which is infiltrated with lymphocytes amidst elastic and reticular fibres.

* '''Submucosa''' - contains loose connective tissue and mixed serous and mucous glands.

* '''Muscularis''' - contains involuntary trachealis smooth muscle which allows movement of trachea and changes shape during swallowing.

* '''Adventitia''' - contains collagenous connective tissue bands and C-shaped hyaline cartilage rings.

As the bronchi branch off some changes in their histology occurs, including:

1. Cartilage rings are reduced to irregular plates of cartilage.

2. A circular band of smooth muscle develops between cartilage and mucosa.

3. Fewer goblet cells.

4. Epithelium height reduces and becomes simple columnar with fewer cilia.

Bronchioles differ in that they do not have cartilaginous plates, have an increased size of circular smooth muscle, have ciliated or non-ciliated low cuboidal epithelium and lack goblet cells.

Terminal bronchioles are the final air passageways of the conduction zone and display a reduction in the muscle layer and the lamina propria is thinner. The epithelium is also cuboidal.

The respiratory zone contains the respiratory bronchiole, alveolar ducts and sacs and alveoli.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png|thumb|Lung Cardiovasculature]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" |[[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref name="PMID28144783 "><pubmed>28144783 </pubmed></ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref name="PMID7850362"><pubmed>7850362</pubmed></ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref name="PMID5501462"><pubmed>5501462</pubmed></ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref name="PMID950075"><pubmed>950075</pubmed></ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | [[File:Pseudoglandular epithelium.gif|thumb| Epithelial structures in Pseudoglandular, Canalicular and Saccular stages of lung development <ref name="PMID28144783"/>]]

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells which preceeds the formation of the air-blood tissue barrier. <ref name="PMID20691848"><pubmed>20691848</pubmed></ref> At the end of this stage it is possible to distinguish between conducting and respiratory airways.
| width="65" | In 1971, Edward A. Boyden published an article detailing for the first time the detailed structure of a pulmonary acinus. The presence of these acini are important for the distinction between conducting and respiratory airways in the Canalicular stage.
| width="65" | [[File:Air blood barrier.gif|thumb| Change in pulmonary epithelium consequently leading to formation of the air-blood barrier in the developing lung <ref name="PMID28144783"/>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular primary septa <ref name="PMID6370120"><pubmed>6370120</pubmed></ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. Babies born prematurely that have reached this stage of lung development have a chance of surviving, directly relating to the number of lamellar bodies present.<ref> Rothstein, P. 2017. Lung Development. Columbia University. Retrieved from :http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" | In 1921, Von Neergaard discovered the function of pulmonary surfactant in newborns but the importance of his work was not recognised until the 1950s when it was rediscovered. <ref name="PMID9813256"><pubmed>9813256</pubmed></ref>The rediscovery was significant for the further understanding of Respiratory Distress Syndrome (RDS); in 1959, Avery and Mead discovered that premature infants suffering from RDS were more often surfactant deficient than not.<ref name="PMID13649082"><pubmed>13649082</pubmed></ref> This boosted research in the area of surfactant.
| width="65" | [[File:Alveolus.png|thumb|Structure of an alveolus including the structures of both Pneumocyte I and II, surfactant and lamellar body <ref name="PMID2195058"><pubmed>2195058</pubmed></ref>]]

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood. This stage involves the formation of a secondary septa and its fusing with the primary septa to produce a more effective single-layered capillary network. This is part of a process called microvascular maturation. <ref name="PMID28144783"/> In the classical mode of alveolarization, it was believed that after the formation of the new septa that alveolarizatoin ceased. However, more recent evidence has proved otherwise and shown alveolarization occurs from this stage and continues post-natally, this was termed "Continued alveolarization". The differences in these are shown in the accompanying figure. Once a child is born, massive changes occur in lung development. The alveoli formed prenatally, sometimes referred to as "primitive saccules", continue to mature and fully form up until a child is 8-10 years old. At birth, these primitive saccules number approximately 20 million and continue to develop to reach numbers of 300 million alveoli by childhood.<ref name="PMID7850362"/>
| width="65" | The Alveolarization stage of lung development has been increasingly well documented in the recent years corresponding to increasing technological advances. Traditionally, the counting of alveoli was done by assuming the structure of the alveolus and using a general equation to calculate total alveoli volume. This approach by Weibel and Gomez in 1962 set the stage for the first method of counting alveoli. <ref name="PMID14005589"><pubmed>14005589</pubmed></ref>. In 2004, Hyde et al. used a method of unbiased disector princple to estimate the Euler characteristic (a polyhedron formula) which gives an estimate of alveolar volume in the lung or in a certain section of it. An important improvement here is the implementation of an unbiased principle for the estimates made. <ref name="PMID14983516"><pubmed>14983516</pubmed></ref>
| width="65" | [[File:Alveolarization.gif|thumb| Classic and continued alveolarization in the final stage of lung development<ref name="PMID28144783"/>]]
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px|centre]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg|centre]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

===Alveolus: the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, looked at the maternal over-nutrition in the regulation of surfactant in sheep, and suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth, the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung.

One study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume with growth of the epithelial tree adapting to fill the available space in the mesenchyme.

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Mouse models have been widely used in the genetic field of research as it shares many common features with the human genome. By manipulating the gene pool, we are able to examine the physiology and anatomy of mice offsprings with selected gene characteristics. The low costs of mice, short reproductive cycle and lifespan make mice a perfect animal model to observe lung embryology. Some disadvantages that come with mice models are that they are significantly smaller than humans and have immunological differences, such as a lack of IL-8.

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: GATA6, Bmp, Wnt7b, Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
Sox 2 is a Sry related HMG in a conserved family of transcription factors, where different Sox proteins will regulate different gene targets. SOX genes have always had a major role in the modulation of fetal development and cell differentiation. In particular, Sox 2 has been seen in neurogenesis, neural stem cells and hair cells in the cochlea. For the lung specifically, Sox 2 has been suggested to have a role in branching morphogenesis and early fetal lung development. In animals lung models, overexpressed Sox 2 lead to early differentiation in cells and premature commitment. It was shown to drive precursor-like cells to a commited state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif and modulates gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium. To analyse the role of GATA6 in fetal lung development, expression patterns of lungs in early development were examined suggesting that this transcription factor is involved in branching morphogenesis. Chimeric embryos were produced from ES cells and lungs were dissected at different E days. In the chimeric lungs of mouse in earlier E days had smaller and less lung buds compared to non-chimeric lungs and had fewer branches. In defective GATA6 endoderm, the abnormal phenotype displayed was due to abnormal branching morphogenesis as a result of delayed epithelial differentiation.

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===

[[File:MAS.jpg|250px|thumb|right|Lateral view of a chest radiography of an infant with MAS.]]

Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image. </ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

[[File:CPAMXCT.jpg|350px|thumb|right|Chest radiography and contrast CT imaging of the lungs of a 36-year old woman diagnosed with CPAM.]]

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

Cystic fibrosis (CF) is a disease caused an extreme functional deficiency of the cystic fibrosis trans-membrane conductance regulator (CFTR) protein. It is found in high numbers in epithelial cells that line the cylindrical structures of tissue that often secrete fluids rich in mucus, such as the pancreas and the lungs. Out of all the tissues, the airways have one of the highest amount of CFTR. With the absence of functional CFTR in the lungs, there is defective chloride and bicarbonate secretion into the alveolar secretions. This causes the pH of the airway surface fluid to drop and also prevents secretion of mucus strands from glands. This results in a condition known as CF lung disease. <ref name="PMID25814049"><pubmed>25814049</pubmed></ref>

====Cystic Fibrosis Lung Disease====

This disease is identified by early colonisation and infection of the airways. Due to the acidic conditions of the CF airway surfaces, there is often a significant flaw in the baby's anti-bacterial defences. This leads to a very rapid onset of infection and the resulting inflammatory response is very critical.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> The usual culprits are Staphylococcus aureus and Pseusdomonas aeruginosa, which when mucoid, becomes the dominant pathogen that attacks CF lung tissues.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref> The chronic airway and systemic inflammation that occurs as a result would then lead to tissue destruction and respiratory failure.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> In fact, respiratory failure secondary to lung damage is the usually cause of death for CF patients with most of the damage caused arising from the inflammation instead of the actual bacteria.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref>

==Future questions==

==Glossary==
{|
|-bgcolor="#FBA08D"
| width="150" |<center>'''Term''' </center>
| width="350" |<center>'''Definition'''</center>
|-
| '''Alveoli''' || Microscopic air sacs that inflate and allow respiratory function in the lungs; they are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs.
|- bgcolor="#F2BFB5"
| '''Bronchiole''' || Branchings that form off the bronchus in the lungs and continue to divide into alveoli
|-
| '''Bronchus''' || Two main divisions that that divide from the trachea and further into bronchioles
|-bgcolor="#F2BFB5"
| '''Cilia''' || Microscopic hair-like extensions of epithelia that provide propulsion
|-
| '''Fibroblast Growth Factor (FGF10)''' || serves as a signalling cue for epithelium outgrowth in the mesenchyme.
|-bgcolor="#F2BFB5"
| '''Gastrulation''' || A phase of the embryonic period that sees the formation of the three Germ layers
|-
| '''Germ layers''' || There are three germ layers formed at the end of gastrulation; the ectoderm (responsible for the epidermis, nervous system and neural crest), the endoderm (responsible for epithelium of the respiratory and digestive systems) and the mesoderm (responsible for connective tissues).
|-bgcolor="#F2BFB5"
| '''Goblet Cells''' || Seen microscopically in epithelia and secrete mucus to coat lining of respiratory tract
|-
| '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' || interacts with SHH in order to produce epthelial cells and lung morphogenesis
|-bgcolor="#F2BFB5"
| '''Interstitium''' || Spaces between organs or tissues; in this page, used to refer to the space between pulmonary epithelia and vascular system
|-
| '''Mesenchyme''' || Unorganised connective tissue commonly found in embryonic development, mainly comprised of ground substance
|-bgcolor="#F2BFB5"
| '''Parenchyma''' || The functional cells of an organ or tissue
|-
| '''Planar and orthogonal branching''' || Planar branching refers to branching in one plane of reference whereas orthogonal branching is branching at right angles
|-bgcolor="#F2BFB5"
| '''Septum''' || Plural form: Septa, a division between two chambers; in this page used as reference to the divisions of the respiratory lobes in early lung development
|-
| '''Sonic Hedgehog (SHH)''' || produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.
|-bgcolor="#F2BFB5"
| '''Sox9''' || promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix.
|-
| '''Tachypnoea''' || Atypical rapid breathing
|-bgcolor="#F2BFB5"
| '''Terminal broncihole''' || the final air passageways of the conduction zone; they display a reduction in the muscle layer and a thinner lamina propria
|-
| '''Type I Alveolar Cells''' || Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.
|- bgcolor="#F2BFB5"
| '''Type II Alveolar Cells''' || Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.
|-
|'''Wnt7b''' || a protein encoding Wnt7b protein, in charge of deciding cell fate and patterning during embryogenesis
|}

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-24T10:44:06Z

Z5178462: /* Meconium Aspiration Syndrome */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth. Although the lungs are not functional until birth, they must undergo a range of development and growth in order to function post-natally. This wiki will aim to give an overview of the anatomy and histology of the lung, the timeline of development, signalling processes that occur within the lung as well as any abnormalities that can occur during lung development.

===Lung Anatomy===

[[File:Lunganatomy.png|thumb|Lung Anatomy]]
To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is '''ciliated pseudostratified epithelium'''.

Each lung receives air through these '''primary bronchi'''. As these primary bronchi enter the lungs, they branch into smaller '''secondary bronchi''' which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains '''cilia''' and '''goblet cells'''. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. '''Bronchioles''' are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller '''terminal bronchioles'''. They are the smallest tubes in lungs and terminate at the '''alveoli'''. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===
[[File:Lung histology.png|thumb|Lung histology]]

The diagram shows the histology of the lung.

Bronchi have similar histological layers including:

* '''Mucosa''' - contains respiratory epithelium which is characterised as pseudostratified ciliated columnar epithelium with goblet cells. It also contains a lamina propria which is infiltrated with lymphocytes amidst elastic and reticular fibres.

* '''Submucosa''' - contains loose connective tissue and mixed serous and mucous glands.

* '''Muscularis''' - contains involuntary trachealis smooth muscle which allows movement of trachea and changes shape during swallowing.

* '''Adventitia''' - contains collagenous connective tissue bands and C-shaped hyaline cartilage rings.

As the bronchi branch off some changes in their histology occurs, including:

1. Cartilage rings are reduced to irregular plates of cartilage.

2. A circular band of smooth muscle develops between cartilage and mucosa.

3. Fewer goblet cells.

4. Epithelium height reduces and becomes simple columnar with fewer cilia.

Bronchioles differ in that they do not have cartilaginous plates, have an increased size of circular smooth muscle, have ciliated or non-ciliated low cuboidal epithelium and lack goblet cells.

Terminal bronchioles are the final air passageways of the conduction zone and display a reduction in the muscle layer and the lamina propria is thinner. The epithelium is also cuboidal.

The respiratory zone contains the respiratory bronchiole, alveolar ducts and sacs and alveoli.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png|thumb|Lung Cardiovasculature]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" |[[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref name="PMID28144783 "><pubmed>28144783 </pubmed></ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref name="PMID7850362"><pubmed>7850362</pubmed></ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref name="PMID5501462"><pubmed>5501462</pubmed></ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref name="PMID950075"><pubmed>950075</pubmed></ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | [[File:Pseudoglandular epithelium.gif|thumb| Epithelial structures in Pseudoglandular, Canalicular and Saccular stages of lung development <ref name="PMID28144783"/>]]

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells which preceeds the formation of the air-blood tissue barrier. <ref name="PMID20691848"><pubmed>20691848</pubmed></ref> At the end of this stage it is possible to distinguish between conducting and respiratory airways.
| width="65" | In 1971, Edward A. Boyden published an article detailing for the first time the detailed structure of a pulmonary acinus. The presence of these acini are important for the distinction between conducting and respiratory airways in the Canalicular stage.
| width="65" | [[File:Air blood barrier.gif|thumb| Change in pulmonary epithelium consequently leading to formation of the air-blood barrier in the developing lung <ref name="PMID28144783"/>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular primary septa <ref name="PMID6370120"><pubmed>6370120</pubmed></ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. Babies born prematurely that have reached this stage of lung development have a chance of surviving, directly relating to the number of lamellar bodies present.<ref> Rothstein, P. 2017. Lung Development. Columbia University. Retrieved from :http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" | In 1921, Von Neergaard discovered the function of pulmonary surfactant in newborns but the importance of his work was not recognised until the 1950s when it was rediscovered. <ref name="PMID9813256"><pubmed>9813256</pubmed></ref>The rediscovery was significant for the further understanding of Respiratory Distress Syndrome (RDS); in 1959, Avery and Mead discovered that premature infants suffering from RDS were more often surfactant deficient than not.<ref name="PMID13649082"><pubmed>13649082</pubmed></ref> This boosted research in the area of surfactant.
| width="65" | [[File:Alveolus.png|thumb|Structure of an alveolus including the structures of both Pneumocyte I and II, surfactant and lamellar body <ref name="PMID2195058"><pubmed>2195058</pubmed></ref>]]

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood. This stage involves the formation of a secondary septa and its fusing with the primary septa to produce a more effective single-layered capillary network. This is part of a process called microvascular maturation. <ref name="PMID28144783"/> In the classical mode of alveolarization, it was believed that after the formation of the new septa that alveolarizatoin ceased. However, more recent evidence has proved otherwise and shown alveolarization occurs from this stage and continues post-natally, this was termed "Continued alveolarization". The differences in these are shown in the accompanying figure. Once a child is born, massive changes occur in lung development. The alveoli formed prenatally, sometimes referred to as "primitive saccules", continue to mature and fully form up until a child is 8-10 years old. At birth, these primitive saccules number approximately 20 million and continue to develop to reach numbers of 300 million alveoli by childhood.<ref name="PMID7850362"/>
| width="65" | The Alveolarization stage of lung development has been increasingly well documented in the recent years corresponding to increasing technological advances. Traditionally, the counting of alveoli was done by assuming the structure of the alveolus and using a general equation to calculate total alveoli volume. This approach by Weibel and Gomez in 1962 set the stage for the first method of counting alveoli. <ref name="PMID14005589"><pubmed>14005589</pubmed></ref>. In 2004, Hyde et al. used a method of unbiased disector princple to estimate the Euler characteristic (a polyhedron formula) which gives an estimate of alveolar volume in the lung or in a certain section of it. An important improvement here is the implementation of an unbiased principle for the estimates made. <ref name="PMID14983516"><pubmed>14983516</pubmed></ref>
| width="65" | [[File:Alveolarization.gif|thumb| Classic and continued alveolarization in the final stage of lung development<ref name="PMID28144783"/>]]
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px|centre]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg|centre]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

===Alveolus: the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, looked at the maternal over-nutrition in the regulation of surfactant in sheep, and suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth, the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.
Dagmar Iber, Denis Menshykau The control of branching morphogenesis. Open Biol: 2013, 3(9);130088 PubMed 24004663

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung.
Dagmar Iber, Denis Menshykau The control of branching morphogenesis. Open Biol: 2013, 3(9);130088 PubMed 24004663

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: GATA6, Bmp, Wnt7b, Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
Sox 2 is a Sry related HMG in a conserved family of transcription factors, where different Sox proteins will regulate different gene targets. SOX genes have always had a major role in the modulation of fetal development and cell differentiation. In particular, Sox 2 has been seen in neurogenesis, neural stem cells and hair cells in the cochlea. For the lung specifically, Sox 2 has been suggested to have a role in branching morphogenesis and early fetal lung development. In animals lung models, overexpressed Sox 2 lead to early differentiation in cells and premature commitment. It was shown to drive precursor-like cells to a commited state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif and modulates gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium. To analyse the role of GATA6 in fetal lung development, expression patterns of lungs in early development were examined suggesting that this transcription factor is involved in branching morphogenesis. Chimeric embryos were produced from ES cells and lungs were dissected at different E days. In the chimeric lungs of mouse in earlier E days had smaller and less lung buds compared to non-chimeric lungs and had fewer branches. In defective GATA6 endoderm, the abnormal phenotype displayed was due to abnormal branching morphogenesis as a result of delayed epithelial differentiation.

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===

[[File:MAS.jpg|250px|thumb|right|Lateral view of a chest radiography of an infant with MAS.]]

Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

[[File:CPAMXCT.jpg|350px|thumb|right|Chest radiography and contrast CT imaging of the lungs of a 36-year old woman diagnosed with CPAM.]]

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

Cystic fibrosis (CF) is a disease caused an extreme functional deficiency of the cystic fibrosis trans-membrane conductance regulator (CFTR) protein. It is found in high numbers in epithelial cells that line the cylindrical structures of tissue that often secrete fluids rich in mucus, such as the pancreas and the lungs. Out of all the tissues, the airways have one of the highest amount of CFTR. With the absence of functional CFTR in the lungs, there is defective chloride and bicarbonate secretion into the alveolar secretions. This causes the pH of the airway surface fluid to drop and also prevents secretion of mucus strands from glands. This results in a condition known as CF lung disease. <ref name="PMID25814049"><pubmed>25814049</pubmed></ref>

====Cystic Fibrosis Lung Disease====

This disease is identified by early colonisation and infection of the airways. Due to the acidic conditions of the CF airway surfaces, there is often a significant flaw in the baby's anti-bacterial defences. This leads to a very rapid onset of infection and the resulting inflammatory response is very critical.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> The usual culprits are Staphylococcus aureus and Pseusdomonas aeruginosa, which when mucoid, becomes the dominant pathogen that attacks CF lung tissues.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref> The chronic airway and systemic inflammation that occurs as a result would then lead to tissue destruction and respiratory failure.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> In fact, respiratory failure secondary to lung damage is the usually cause of death for CF patients with most of the damage caused arising from the inflammation instead of the actual bacteria.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref>

==Future questions==

==Glossary==
{|
|-bgcolor="#FBA08D"
| width="150" |<center>'''Term''' </center>
| width="350" |<center>'''Definition'''</center>
|-
| '''Alveoli''' || Microscopic air sacs that inflate and allow respiratory function in the lungs; they are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs.
|- bgcolor="#F2BFB5"
| '''Bronchiole''' || Branchings that form off the bronchus in the lungs and continue to divide into alveoli
|-
| '''Bronchus''' || Two main divisions that that divide from the trachea and further into bronchioles
|-bgcolor="#F2BFB5"
| '''Cilia''' || Microscopic hair-like extensions of epithelia that provide propulsion
|-
| '''Fibroblast Growth Factor (FGF10)''' || serves as a signalling cue for epithelium outgrowth in the mesenchyme.
|-bgcolor="#F2BFB5"
| '''Gastrulation''' || A phase of the embryonic period that sees the formation of the three Germ layers
|-
| '''Germ layers''' || There are three germ layers formed at the end of gastrulation; the ectoderm (responsible for the epidermis, nervous system and neural crest), the endoderm (responsible for epithelium of the respiratory and digestive systems) and the mesoderm (responsible for connective tissues).
|-bgcolor="#F2BFB5"
| '''Goblet Cells''' || Seen microscopically in epithelia and secrete mucus to coat lining of respiratory tract
|-
| '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' || interacts with SHH in order to produce epthelial cells and lung morphogenesis
|-bgcolor="#F2BFB5"
| '''Interstitium''' || Spaces between organs or tissues; in this page, used to refer to the space between pulmonary epithelia and vascular system
|-
| '''Mesenchyme''' || Unorganised connective tissue commonly found in embryonic development, mainly comprised of ground substance
|-bgcolor="#F2BFB5"
| '''Parenchyma''' || The functional cells of an organ or tissue
|-
| '''Planar and orthogonal branching''' || Planar branching refers to branching in one plane of reference whereas orthogonal branching is branching at right angles
|-bgcolor="#F2BFB5"
| '''Septum''' || Plural form: Septa, a division between two chambers; in this page used as reference to the divisions of the respiratory lobes in early lung development
|-
| '''Sonic Hedgehog (SHH)''' || produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.
|-bgcolor="#F2BFB5"
| '''Sox9''' || promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix.
|-
| '''Tachypnoea''' || Atypical rapid breathing
|-bgcolor="#F2BFB5"
| '''Terminal broncihole''' || the final air passageways of the conduction zone; they display a reduction in the muscle layer and a thinner lamina propria
|-
| '''Type I Alveolar Cells''' || Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.
|- bgcolor="#F2BFB5"
| '''Type II Alveolar Cells''' || Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.
|-
|'''Wnt7b''' || a protein encoding Wnt7b protein, in charge of deciding cell fate and patterning during embryogenesis
|}

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-24T10:42:05Z

Z5178462: /* Abnormal development */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth. Although the lungs are not functional until birth, they must undergo a range of development and growth in order to function post-natally. This wiki will aim to give an overview of the anatomy and histology of the lung, the timeline of development, signalling processes that occur within the lung as well as any abnormalities that can occur during lung development.

===Lung Anatomy===

[[File:Lunganatomy.png|thumb|Lung Anatomy]]
To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is '''ciliated pseudostratified epithelium'''.

Each lung receives air through these '''primary bronchi'''. As these primary bronchi enter the lungs, they branch into smaller '''secondary bronchi''' which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains '''cilia''' and '''goblet cells'''. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. '''Bronchioles''' are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller '''terminal bronchioles'''. They are the smallest tubes in lungs and terminate at the '''alveoli'''. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===
[[File:Lung histology.png|thumb|Lung histology]]

The diagram shows the histology of the lung.

Bronchi have similar histological layers including:

* '''Mucosa''' - contains respiratory epithelium which is characterised as pseudostratified ciliated columnar epithelium with goblet cells. It also contains a lamina propria which is infiltrated with lymphocytes amidst elastic and reticular fibres.

* '''Submucosa''' - contains loose connective tissue and mixed serous and mucous glands.

* '''Muscularis''' - contains involuntary trachealis smooth muscle which allows movement of trachea and changes shape during swallowing.

* '''Adventitia''' - contains collagenous connective tissue bands and C-shaped hyaline cartilage rings.

As the bronchi branch off some changes in their histology occurs, including:

1. Cartilage rings are reduced to irregular plates of cartilage.

2. A circular band of smooth muscle develops between cartilage and mucosa.

3. Fewer goblet cells.

4. Epithelium height reduces and becomes simple columnar with fewer cilia.

Bronchioles differ in that they do not have cartilaginous plates, have an increased size of circular smooth muscle, have ciliated or non-ciliated low cuboidal epithelium and lack goblet cells.

Terminal bronchioles are the final air passageways of the conduction zone and display a reduction in the muscle layer and the lamina propria is thinner. The epithelium is also cuboidal.

The respiratory zone contains the respiratory bronchiole, alveolar ducts and sacs and alveoli.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png|thumb|Lung Cardiovasculature]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" |[[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref name="PMID28144783 "><pubmed>28144783 </pubmed></ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref name="PMID7850362"><pubmed>7850362</pubmed></ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref name="PMID5501462"><pubmed>5501462</pubmed></ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref name="PMID950075"><pubmed>950075</pubmed></ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | [[File:Pseudoglandular epithelium.gif|thumb| Epithelial structures in Pseudoglandular, Canalicular and Saccular stages of lung development <ref name="PMID28144783"/>]]

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells which preceeds the formation of the air-blood tissue barrier. <ref name="PMID20691848"><pubmed>20691848</pubmed></ref> At the end of this stage it is possible to distinguish between conducting and respiratory airways.
| width="65" | In 1971, Edward A. Boyden published an article detailing for the first time the detailed structure of a pulmonary acinus. The presence of these acini are important for the distinction between conducting and respiratory airways in the Canalicular stage.
| width="65" | [[File:Air blood barrier.gif|thumb| Change in pulmonary epithelium consequently leading to formation of the air-blood barrier in the developing lung <ref name="PMID28144783"/>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular primary septa <ref name="PMID6370120"><pubmed>6370120</pubmed></ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. Babies born prematurely that have reached this stage of lung development have a chance of surviving, directly relating to the number of lamellar bodies present.<ref> Rothstein, P. 2017. Lung Development. Columbia University. Retrieved from :http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" | In 1921, Von Neergaard discovered the function of pulmonary surfactant in newborns but the importance of his work was not recognised until the 1950s when it was rediscovered. <ref name="PMID9813256"><pubmed>9813256</pubmed></ref>The rediscovery was significant for the further understanding of Respiratory Distress Syndrome (RDS); in 1959, Avery and Mead discovered that premature infants suffering from RDS were more often surfactant deficient than not.<ref name="PMID13649082"><pubmed>13649082</pubmed></ref> This boosted research in the area of surfactant.
| width="65" | [[File:Alveolus.png|thumb|Structure of an alveolus including the structures of both Pneumocyte I and II, surfactant and lamellar body <ref name="PMID2195058"><pubmed>2195058</pubmed></ref>]]

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood. This stage involves the formation of a secondary septa and its fusing with the primary septa to produce a more effective single-layered capillary network. This is part of a process called microvascular maturation. <ref name="PMID28144783"/> In the classical mode of alveolarization, it was believed that after the formation of the new septa that alveolarizatoin ceased. However, more recent evidence has proved otherwise and shown alveolarization occurs from this stage and continues post-natally, this was termed "Continued alveolarization". The differences in these are shown in the accompanying figure. Once a child is born, massive changes occur in lung development. The alveoli formed prenatally, sometimes referred to as "primitive saccules", continue to mature and fully form up until a child is 8-10 years old. At birth, these primitive saccules number approximately 20 million and continue to develop to reach numbers of 300 million alveoli by childhood.<ref name="PMID7850362"/>
| width="65" | The Alveolarization stage of lung development has been increasingly well documented in the recent years corresponding to increasing technological advances. Traditionally, the counting of alveoli was done by assuming the structure of the alveolus and using a general equation to calculate total alveoli volume. This approach by Weibel and Gomez in 1962 set the stage for the first method of counting alveoli. <ref name="PMID14005589"><pubmed>14005589</pubmed></ref>. In 2004, Hyde et al. used a method of unbiased disector princple to estimate the Euler characteristic (a polyhedron formula) which gives an estimate of alveolar volume in the lung or in a certain section of it. An important improvement here is the implementation of an unbiased principle for the estimates made. <ref name="PMID14983516"><pubmed>14983516</pubmed></ref>
| width="65" | [[File:Alveolarization.gif|thumb| Classic and continued alveolarization in the final stage of lung development<ref name="PMID28144783"/>]]
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px|centre]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg|centre]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

===Alveolus: the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, looked at the maternal over-nutrition in the regulation of surfactant in sheep, and suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth, the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.
Dagmar Iber, Denis Menshykau The control of branching morphogenesis. Open Biol: 2013, 3(9);130088 PubMed 24004663

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung.
Dagmar Iber, Denis Menshykau The control of branching morphogenesis. Open Biol: 2013, 3(9);130088 PubMed 24004663

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: GATA6, Bmp, Wnt7b, Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
Sox 2 is a Sry related HMG in a conserved family of transcription factors, where different Sox proteins will regulate different gene targets. SOX genes have always had a major role in the modulation of fetal development and cell differentiation. In particular, Sox 2 has been seen in neurogenesis, neural stem cells and hair cells in the cochlea. For the lung specifically, Sox 2 has been suggested to have a role in branching morphogenesis and early fetal lung development. In animals lung models, overexpressed Sox 2 lead to early differentiation in cells and premature commitment. It was shown to drive precursor-like cells to a commited state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif and modulates gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium. To analyse the role of GATA6 in fetal lung development, expression patterns of lungs in early development were examined suggesting that this transcription factor is involved in branching morphogenesis. Chimeric embryos were produced from ES cells and lungs were dissected at different E days. In the chimeric lungs of mouse in earlier E days had smaller and less lung buds compared to non-chimeric lungs and had fewer branches. In defective GATA6 endoderm, the abnormal phenotype displayed was due to abnormal branching morphogenesis as a result of delayed epithelial differentiation.

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===

[[File:MAS.jpg|350px|thumb|right|Lateral view of a chest radiography of an infant with MAS.]]

Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

[[File:CPAMXCT.jpg|350px|thumb|right|Chest radiography and contrast CT imaging of the lungs of a 36-year old woman diagnosed with CPAM.]]

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

Cystic fibrosis (CF) is a disease caused an extreme functional deficiency of the cystic fibrosis trans-membrane conductance regulator (CFTR) protein. It is found in high numbers in epithelial cells that line the cylindrical structures of tissue that often secrete fluids rich in mucus, such as the pancreas and the lungs. Out of all the tissues, the airways have one of the highest amount of CFTR. With the absence of functional CFTR in the lungs, there is defective chloride and bicarbonate secretion into the alveolar secretions. This causes the pH of the airway surface fluid to drop and also prevents secretion of mucus strands from glands. This results in a condition known as CF lung disease. <ref name="PMID25814049"><pubmed>25814049</pubmed></ref>

====Cystic Fibrosis Lung Disease====

This disease is identified by early colonisation and infection of the airways. Due to the acidic conditions of the CF airway surfaces, there is often a significant flaw in the baby's anti-bacterial defences. This leads to a very rapid onset of infection and the resulting inflammatory response is very critical.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> The usual culprits are Staphylococcus aureus and Pseusdomonas aeruginosa, which when mucoid, becomes the dominant pathogen that attacks CF lung tissues.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref> The chronic airway and systemic inflammation that occurs as a result would then lead to tissue destruction and respiratory failure.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> In fact, respiratory failure secondary to lung damage is the usually cause of death for CF patients with most of the damage caused arising from the inflammation instead of the actual bacteria.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref>

==Future questions==

==Glossary==
{|
|-bgcolor="#FBA08D"
| width="150" |<center>'''Term''' </center>
| width="350" |<center>'''Definition'''</center>
|-
| '''Alveoli''' || Microscopic air sacs that inflate and allow respiratory function in the lungs; they are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs.
|- bgcolor="#F2BFB5"
| '''Bronchiole''' || Branchings that form off the bronchus in the lungs and continue to divide into alveoli
|-
| '''Bronchus''' || Two main divisions that that divide from the trachea and further into bronchioles
|-bgcolor="#F2BFB5"
| '''Cilia''' || Microscopic hair-like extensions of epithelia that provide propulsion
|-
| '''Fibroblast Growth Factor (FGF10)''' || serves as a signalling cue for epithelium outgrowth in the mesenchyme.
|-bgcolor="#F2BFB5"
| '''Gastrulation''' || A phase of the embryonic period that sees the formation of the three Germ layers
|-
| '''Germ layers''' || There are three germ layers formed at the end of gastrulation; the ectoderm (responsible for the epidermis, nervous system and neural crest), the endoderm (responsible for epithelium of the respiratory and digestive systems) and the mesoderm (responsible for connective tissues).
|-bgcolor="#F2BFB5"
| '''Goblet Cells''' || Seen microscopically in epithelia and secrete mucus to coat lining of respiratory tract
|-
| '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' || interacts with SHH in order to produce epthelial cells and lung morphogenesis
|-bgcolor="#F2BFB5"
| '''Interstitium''' || Spaces between organs or tissues; in this page, used to refer to the space between pulmonary epithelia and vascular system
|-
| '''Mesenchyme''' || Unorganised connective tissue commonly found in embryonic development, mainly comprised of ground substance
|-bgcolor="#F2BFB5"
| '''Parenchyma''' || The functional cells of an organ or tissue
|-
| '''Planar and orthogonal branching''' || Planar branching refers to branching in one plane of reference whereas orthogonal branching is branching at right angles
|-bgcolor="#F2BFB5"
| '''Septum''' || Plural form: Septa, a division between two chambers; in this page used as reference to the divisions of the respiratory lobes in early lung development
|-
| '''Sonic Hedgehog (SHH)''' || produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.
|-bgcolor="#F2BFB5"
| '''Sox9''' || promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix.
|-
| '''Tachypnoea''' || Atypical rapid breathing
|-bgcolor="#F2BFB5"
| '''Terminal broncihole''' || the final air passageways of the conduction zone; they display a reduction in the muscle layer and a thinner lamina propria
|-
| '''Type I Alveolar Cells''' || Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.
|- bgcolor="#F2BFB5"
| '''Type II Alveolar Cells''' || Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.
|-
|'''Wnt7b''' || a protein encoding Wnt7b protein, in charge of deciding cell fate and patterning during embryogenesis
|}

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

File:MAS.jpg

2017-10-24T10:39:18Z

Z5178462: /* Meconium Aspiration Syndrome (MAS) */

==Meconium Aspiration Syndrome (MAS)==

This image shows a radiography of the lateral view of an infant that was born through thickly stained meconium liquor. She initially suffered from respiratory distress as a result. The lung radiography shows patch opacity with hyperinflation.

The typical radiological features of MAS are:
*-Coarse infiltrates
*-Widespread consolidation
*-Hyperinflation
*-Pleural effusions, pneumothorax and pneumomediastinum may be present

Original File Name:CXR-MAS Lateral.jpg
http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/CXR/MAS/CXR%20-%20MAS%20Lateral.jpg

Image and Text: National Women's Health at Auckland City Hospital

===Reference===

http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/LungParenchyma.htm

© Crown copyright [2000-2005] Auckland District Health Board
Material featured on this site is subject to Crown copyright protection unless otherwise indicated. The Crown copyright protected material may be reproduced free of charge in any format or media without requiring specific permission.

This is subject to the material being reproduced accurately and not being used in a derogatory manner or in a misleading context. Where the material is being published or issued to others, the source and copyright status must be acknowledged.

The permission to reproduce Crown copyright protected material does not extend to any material on this site that is identified as being the copyright of a third party. Authorisation to reproduce such material must be obtained from the copyright holders concerned.

{{Student Image}}
[[Category:Respiratory]][[Category:Cartoon]]

File:CPAMXCT.jpg

2017-10-24T10:39:09Z

Z5178462: /* Congenital Pulmonary Airway Malformation */

==Congenital Pulmonary Airway Malformation==

Diagnostic imaging of a 36-year old woman diagnosed with CPAM. On the left shows the chest radiography with the arrow pointing to the lobulated medial right upper lobe nodule. The photo on right shows a contrast CT image with another arrow in pointing to the same lobulated medial right upper lobe nodules as seen in the left image, however the CT revealed surrounding cystic hyperlucency.

===References===
<pubmed>PMC4821328</pubmed>

Copyright © 2015 The Authors
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

{{Student Image}}
[[Category:Respiratory]][[Category:Cartoon]]

File:NRDS.jpg

2017-10-24T10:38:15Z

Z5178462: /* Newborn Respiratory Distress Syndrome (NRDS) */

==Newborn Respiratory Distress Syndrome (NRDS)==

NRDS is also known as Hyaline Membrane Disease or Surfactant deficiency.

The typical radiological features of Surfactant Deficiency are:
*-Small volume lungs
*-Homogenous "ground glass" opacity
*-Air bronchograms

This image is taken after surfactant administration but still shows that the heart is completely concealed by the diffused, homogenous lung fields.

Original File Name:RDS_IPPV.jpg http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/CXR/RDS/RDS_IPPV.jpg

Image and Text: National Women's Health at Auckland City Hospital

===Reference===

http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/LungParenchyma.htm

© Crown copyright [2000-2005] Auckland District Health Board
Material featured on this site is subject to Crown copyright protection unless otherwise indicated. The Crown copyright protected material may be reproduced free of charge in any format or media without requiring specific permission.

This is subject to the material being reproduced accurately and not being used in a derogatory manner or in a misleading context. Where the material is being published or issued to others, the source and copyright status must be acknowledged.

The permission to reproduce Crown copyright protected material does not extend to any material on this site that is identified as being the copyright of a third party. Authorisation to reproduce such material must be obtained from the copyright holders concerned.

{{Student Image}}
[[Category:Respiratory]][[Category:Cartoon]]

File:MAS.jpg

2017-10-24T10:36:44Z

Z5178462: /* Meconium Aspiration Syndrome (MAS) */

File:MAS.jpg

2017-10-24T10:36:25Z

Z5178462: /* Meconium Aspiration Syndrome (MAS) */

==Meconium Aspiration Syndrome (MAS)==

This image shows a radiography of the lateral view of an infant that was born through thickly stained meconium liquor. She initially suffered from respiratory distress as a result. The lung radiography shows patch opacity with hyperinflation.

The typical radiological features of MAS are:
*-Coarse infiltrates
*-Widespread consolidation
*-Hyperinflation
*-Pleural effusions, pneumothorax and pneumomediastinum may be present

Original File Name:CXR-MAS Lateral.jpg

http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/CXR/MAS/CXR%20-%20MAS%20Lateral.jpg

Image and Text: National Women's Health at Auckland City Hospital

===Reference===

http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/LungParenchyma.htm

© Crown copyright [2000-2005] Auckland District Health Board
Material featured on this site is subject to Crown copyright protection unless otherwise indicated. The Crown copyright protected material may be reproduced free of charge in any format or media without requiring specific permission.

This is subject to the material being reproduced accurately and not being used in a derogatory manner or in a misleading context. Where the material is being published or issued to others, the source and copyright status must be acknowledged.

The permission to reproduce Crown copyright protected material does not extend to any material on this site that is identified as being the copyright of a third party. Authorisation to reproduce such material must be obtained from the copyright holders concerned.

File:MAS.jpg

2017-10-24T10:36:05Z

Z5178462: /* Meconium Aspiration Syndrome (MAS) */

File:MAS.jpg

2017-10-24T10:35:36Z

Z5178462: ==Meconium Aspiration Syndrome (MAS)== This image shows a radiography of the lateral view of an infant that was born through thickly stained meconium liquor. She initially suffered from respiratory distress as a result. The lung radiography shows patc...

==Meconium Aspiration Syndrome (MAS)==

This image shows a radiography of the lateral view of an infant that was born through thickly stained meconium liquor. She initially suffered from respiratory distress as a result. The lung radiography shows patch opacity with hyperinflation.

The typical radiological features of MAS are:
*-Coarse infiltrates
*-Widespread consolidation
*-Hyperinflation
*-Pleural effusions, pneumothorax and pneumomediastinum may be present

Original File Name:CXR-MAS Lateral.jpg http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/CXR/MAS/CXR%20-%20MAS%20Lateral.jpg

Image and Text: National Women's Health at Auckland City Hospital

===Reference===

http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/LungParenchyma.htm

© Crown copyright [2000-2005] Auckland District Health Board
Material featured on this site is subject to Crown copyright protection unless otherwise indicated. The Crown copyright protected material may be reproduced free of charge in any format or media without requiring specific permission.

This is subject to the material being reproduced accurately and not being used in a derogatory manner or in a misleading context. Where the material is being published or issued to others, the source and copyright status must be acknowledged.

The permission to reproduce Crown copyright protected material does not extend to any material on this site that is identified as being the copyright of a third party. Authorisation to reproduce such material must be obtained from the copyright holders concerned.

User:Z5178462

2017-10-10T13:44:39Z

Z5178462: /* Peer Reviews */

[[Student Page]]

==Peer Reviews==

===Group 1- Cerebral Cortex===

Overall I find the information provided to be concise and easy to understand. The introduction was great in giving us a brief overview of page. The layout of the early development of the brain and the development of the cerebral cortex was really nice. I like the use of bullet points as this makes it easier to read. Also good amount of referencing is seen in this area. The use of the table is also a nice touch to the page and I like the picture used for E50-55. However, it could help to have another column with pictures for each row. That would help with the understanding of the text. For the anatomy of the cerebral cortex, it seems a little messy and hard to read as it is too point form. Perhaps these could be phrased into proper sentences with certain parts placed into bullet points to make it easier to read. Also, with the anatomy, pictures would be very helpful to aid in the explanation. For the functions of the cerebral cortex, it lists the functional areas but not the functions of those areas. Although it is stated in the video, which is a nice addition to the page, this could be improved by adding short sentences that state these functions that were mentioned as well. For Sections 1.4 and 1.5, references are also needed to state where the information was obtained from. The abnormalities section provides detailed explanations of the various disorders associated with the development of the cerebral cortex. There is also a good amount of pictures used. One thing I noticed was the references which was placed on the top of the section instead of throughout the text.

===Group 2- Kidney===

This wikipage is easy to read and the details provided was informative. The amount of text in each section was just nice and wasnt too overwhelming or insufficient, which was good. Overall, I noticed that the references could be improved. Instead of adding the link at the bottom, the team should use the code to reference such as in the section "Nephron development". Although the use of photos were really helpful and the choice of photos were great in the context they were added in, they were generally inconsistent in either description, reference or copyright information, which should be added to all photos. The anatomical position and kidney structure had clear and concise information and was easily understandable. The timeline of kidney embryology was really nice and I like how it was all 1-2 sentences long, making it really readable. In the section of developmental abnormalities, there is a large amount of text in the beginning that doesnt belong to any abnormality. Perhaps a subheading "Congenital Abnormalities of the Kidney and Urinary Tract" could be added to make it clearer as to what the text is about. Good use of image in each abnormalities though. The article appears to be unfinished but I'm assuming the team will be completing it after this peer review. To sum up, I like the readability of this wikipage and the images chosen, however, referencing and image descriptions could be further looked at for an even better page!

===Group 3- Heart===

This wikipage had all the sections required for this assignment and the team was very detailed in their content. There was also a good amount of referencing. However for certain areas, the entire reference was there instead of just the number. Also, the student numbers should be removed from the page. There was also a good number of photos used and it was good that they had a mix between self-drawn images and images obtained online. However, a way that could improve the images would be to add a description or a caption under each figure so it's easier to know what the picture is about. Some photos in this article lacked description, reference and copyright information, so that could be added as well. For most of the article, I can see that the team carried out a great amount of research for this topic, however it was a little difficult to understand some parts as they were very lengthy and slightly too content heavy. For the developmental timeline, the use of a table was good but the information could be presented in a more concise manner and the headings could be slightly more prominent to make it more readable. The signalling processes was also very well researched but quite lengthy, perhaps a few main signalling pathways could be chosen instead. For the abnormal developments, each abnormalities were well researched on. Perhaps images could be added to show the abnormalities and also maybe one or two more defects would be good. Overall, I think this group did a great job in researching and providing information on this wikipage. Maybe with a bit of tweaking here and there to make it more concise and readable, this wikipage would make a really good project.

===Group 4- Eye===

Overall, this wikipage is pretty incomplete. However, that has been mentioned several times by the team, so i'm sure they will add on more after the peer review. The page is very neat and the text was quite concise. An introduction could be helpful to introduce what is an eye and what it does in the human body. In the anatomy of the adult eye, it was good that there were images of drawings to show the different parts of the eye, perhaps the drawings could be more clearly labelled with a thinner pen/pencil. Also a description of the image would be good as well. This section was well referenced. For the overview of eye develoment, I like the use of tables as it made it very easy to understand the content. The image (Figure 1.) was also well described and had appropriate copyright information. For the headings of this section, some could be changed such as 1.2 Eye Development, 1.2.1 Timeline of Eye Embryology, 1.2.4 Brief Outline/Description of the Eye Development. The portion on development of the eye components is incomplete, however for the parts that were there, there was not too much text and appropriate referencing. Pictures could be used in this section to improve it. For the congenital anomalies, I like the use of the table for ease of reading and understanding. Perhaps a more detailed description could be included. Also maybe the images could be added into the table as another column to make it neater. Good job so far, I think with some alterations and once they add the rest of the page, it would be a good wikipage! :)

===Group 6- Cerebellum===

Overall, this team's wikipage was really informative. They were detailed yet not too much information was given. There was a good balance with text and pictures. The pictures chosen were all of good quality as well with appropriate description, referencing and copyright information provided. The introduction was a very good brief of the entire page and explained what was to be expected. In the basic anatomy of the cerebellum, the subheadings were really well-defined. However, maybe neural development should be shifted to the developmental section instead. This section was well referenced. I like the use of the table to describe the cerebellum developmental weeks. The images used were really helpful in visualizing what was happening in those weeks. In the abnormalities section, it was short and concise with good picture. Maybe the caption of the photos could be placed together with the photo such as those in the table. This could make the photos look neater. Overall I find that this wikipage was well done, it had a good amount of text and photos and the references were all properly included.

 
{{2017ANAT2341 footer}}

Talk:2017 Group Project 3

2017-10-10T13:44:01Z

Z5178462: /* Peer Review */

{{ANAT2341Project2017discussion}}



==Suggested Starting Places==
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:15, 14 August 2017 (AEST) OK Group 3 below are some starting places.

{{Heart Links}}

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Heart+Development ''Heart Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cardiac+Development ''Cardiac Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Heart+Development ''Heart Development'']

Recent papers

<pubmed limit=5>Heart+Development</pubmed>

==Group Topic Intro==

=Peer Review=

'''Peer review group 3'''

* The project contained both developmental origin, timeline, signalling processes, current research and findings, animals model and abnormal development sections. The project therefore has all the sections which were a requirement for the project.
* Overall, I think the project was good. It was well written, easy to understand as a student, the sections correlated well and the context was good. I especially liked the signalling section, even though some context is missing. I think the idea of of addition a treatment part to project is a good but I could not find it in the project. As mentioned some context is missing in the notch pathway, sonic hedgehog and retinoic acid sections.
* The project has a good introduction. You have a clear idea of what you are about the read, which is nice.
* The layout could be a lot better, I think the picture location could be adjusted. In the developmental origin part, the pictures make the section look very confusing. Some of the subheadings, like the abnormal development is pushed to side by the pictures, so when you scroll down the project you miss it.
* In general, the pictures miss their caption, sources and number. Therefore, you do not know which picture there is referred to when you are reading the project. I miss some more pictures in the developmental sections.
* In the developmental origin section I think the last sentence is very long. You get so much information in one sentence that you sometimes forget what you just read.
* The timeline is easy to read and understand. Could contain some key discoveries.
* Thought the glossary of terms is a nice addition to the project.
* Overall the referencing is good, but in some sections like primary heart field and heart tube formation, the referencing is missing. In some parts the articles/or links is at the bottom of the section, which makes it a little confusing.
* I don’t feel like the primary heart field and heart tube formation correlates very well with the secondary heart field and cardiac looping section. When I start reading the latter I feel like om starting on something completely new instead of continuing reading on the heart developing. I get the feeling I am reading two different persons work, and some work should be put into these sections to make it feel more fluent.

---

Don’t forget to remove the hyperlinks that are under ‘Heart’ at the beginning of the page. Remove student numbers from the page. Add a brief description under images so that readers will understand what the image is showing. Remember to move references that are written in some sections to the ‘References’ subheading. The Notch Pathway is incomplete.

Subheadings and content that have been used show a good understanding of the topic area. The use of a table for the ‘Development Timeline’ shows the teams innovativeness. The use of simple sentences in the table allows readers to understand content simply. References have been done well, they are cited properly. The team have used their own images to show their understanding of the heart. The images that they have used have been properly cited: there are references, copyright statements and the Student Image template. Thorough description of abnormal development, animal models and current research which shows the comprehensive research that was done for the heart. The use of Glossary of Terms is helpful to readers who may not understand what some terms are.

---

Use of headings and subheadings break this complex developmental process in to understandable, clear sections.
The images chosen to reinforce the material are appropriate and I particularly like that time has been taken to draw a number of these.
There does seem to be an awful lot of information, and I wonder if this can be cut down at all. For example there is the section on signaling during development, which is a more complex section to understand. This is greatly helped by the diagrams but I can see that there are additional headings that are yet to have information added. It might be an idea to pick a few signaling pathways that occur and really perfect those. I think it has the potential to become very confusing to the reader otherwise.
It is very useful to the reader that you have included a glossary of terms, however I wonder if it may be more effective if this table is placed at the beginning of the page, or as a link at the top that can be opened up, so as the reader can familirise themselves with the terms prior to reading the page.
The page appears to be referenced extensively throughout and appropriately. Good job

---

Overall, this page has a good structure and was enjoyable to read. The headings and subheadings were clear and made it easier to understand the development process of the Heart. Perhaps it would be better to include relevant background information of the heart before jumping into the developmental process straightaway. There is a good amount of images (and well-drawn images) accompanying the text which aided in understanding the content, however some were not labelled with their appropriate descriptions. Most parts were cited correctly and properly, however some areas weren't cited at all such as "Current Research and Findings and "Cardiac Stem Cells". Also, some references were not done properly, check the "Primary Heart Field and Heart Tube Formation" section. Some sections were left blank, however I assume they will be completed over time. Glossary of terms was clever and made the content easier to understand (the heart is quite complicated to understand). Well done overall.

---

Overall, this page had a finished feel because the page is so heavily packed with information, there are some sections that were not completed. There is however, a lot of information that may leave the reader feeling a bit overwhelmed. Some sections are also hard to understand and comprehend especially due to the heavy use of biotechnological jargon (ie. SMAD-dependent, SMAD-independent pathways, β-catenin). A terminology/glossary section would be extremely helpful for this issue. I'd advise using more images in "Abnormal Development" (ie. x-rays or physical observations of sufferers) to help the reader visualise such abnormalities. Referencing under images should be moved to the references section and should be referenced using the '''''< ref >''' '''< / ref >''''' if in text. Overall, there is a lot of information, some of which is not necessarily important. I'd advise to cut down, make paragraphs more simple and straight to the point, and use images to help the reader visually understand and comprehend.

---

Introduction is very good and explains a lot. Under the heading “Primary heart field and heart tube formation” – the reference at the bottom should be removed.
Secondary heart field and cardiac looping: First sentence doesn’t really make sense, maybe switch it up a bit.
Under current research and findings you have labelled a figure figure 1, when it is not the first figure in your wiki page, seems a little confusing. Images also don’t have appriopriate copyright info, description and referencing. Also figure 2 is placed right in the middle of the sentence, maybe put it to the right so it doesn’t interrupt reading.
Information could be formatted better under the heading atrial septal defect! Maybe some subheadings for the different defects? Same goes with the ventricular septal defect, its easier to read when things are broken up. Glossary is very good!

All the information written on your page is very well written and easily understood.
Images could be labelled better, add a figure to each of them as when you are referring to figure 1 and 2 in your writing, the images aren’t labelled so its hard to tell what image you are referring to.
With references, I don’t like how there is a bunch at the end of some headings? Could be because you still need to read them but looks messy.
There is an overwhelming amount of information, so good job on doing so much research but it was quite tedious to read, not sure if this much information is needed? But it is very hard to fault your wiki page so this might be a bit picky.

---

The introduction is a brief and clear overview of the page. I liked how you acknowledged what your page will explore about the heart development. The “Developmental origin” subheading had good information and good diagrams in addition. However, I would adjust your layout a bit in this section so that the diagrams don’t look so awkward. You could do this by breaking down that second paragraph. The timeline provided a brief overview but I would also suggest adding another column for images. There is also a spelling error on week 5 – it says “srtats” where it should be “starts”.
As you go into “primary heart field and heart tube formation”, “secondary heart field and cardiac looping” and the next few sections, the references appear at the bottom of the sections. You should fix this so that they only appear in the reference list at the end. You could also probably bold “heart tube fusion”, “heart looping” and other terms in your developmental timeline since you explore them in depth.
The “developmental signalling process” subheading is very detailed. Since you also have a few more parts to complete into this section, it might be better to try to minimise some of the text. Your inclusion of current research is good and unique as you explore one paper in depth. However, I would suggest that you find another one or two. The “animal models” subheading should probably have a diagram or two of the referenced research papers if possible. Again with “abnormal development” subheading I would suggest some more images to see what these defects look like and possibly cutting down some text. In “future questions” you might also be able to provide a possible direction research might take to potentially answer this question. Also, you had a very good, long list of references.

---

The page goes through everything required for the project page. It would be nice if the pictures on the page have a figure number and a short title on the figures, so it is easier for the reader to understand what figure belongs to what part of the section. A figure number on the picture makes it able for the writer to refer to a specific picture. There is a good use of tables and self-drawn figures/picture. This makes the page clearer and more readable. There are some references on the page that needs a different formatting, so it is not fully viewed in the sections. It is important that the references are given right after the specific section and not at the bottom of the section.

*'''The Introduction''' section gives a good excitement for the reader before reading the page. This gives an idea of what information to expect from the page. A little section about the anatomy of the heart and a picture could give a better preparation for the reader to understand the developmental part of the heart.
*'''The Development Origin''' section has a bit confusing layout.
*I like that the '''Cardiac Neural Crest and Outflow tract''' sections have a self-drawn picture, but maybe you can draw it a bit clearer, so it is easier to read the writing and understand the figure There is no figure text on the page of the figure.
*'''Current Research And Findings, Animal Models and Abnormal Development:''' These sections have a bit of a messy layout. The context is good, but there I a lot of text and pictures kind of mingling into each other. You could make these sections more separate in the layout.
*'''The Glossary of terms''' helps the reader a lot.

---

The headings were all neat, concise and impressive. It successfully highlighted and sectioned the key topics in the development of the heart. The addition of the technical signalling pathways and the details of the development were well summarised with appropriate references in superscript format. There was a nice variety of visual resources, both hand drawn and externally sourced. Most images have their copyright approval and reference included perfectly, except "Figure 1 Morphological defects in CTCF mutant embryonic hearts" and "Figure 2 - defects of mitochondria in CTCF mutant hearts". There was a nice flow throughout the page through the use of effective paragraph sectioning. The table for the glossary of terms was really useful and neat.

Some of the images didn't have a box around it and these figures were not labelled, this should be easily changed in the edit mode. Some of the hand drawn images were somewhat unclear, due to the writing as well as the rough outline of the heart. Signatures should also be removed. The references were also retained in the bottom of the sections. It was a confusing because it wasn't next to any paragraphs that needed to be referenced. A reference was also repeated in this section.

''For example:''
"This image is based upon Robert H Anderson, Sandra Webb, Nigel A Brown, Wouter Lamers, Antoon Moorman Development of the heart: (3) formation of the ventricular outflow tracts, arterial valves, and intrapericardial arterial trunks. Heart: 2003, 89(9);1110-8 PubMed 12923046

Robert H Anderson, Sandra Webb, Nigel A Brown, Wouter Lamers, Antoon Moorman Development of the heart: (3) formation of the ventricular outflow tracts, arterial valves, and intrapericardial arterial trunks. Heart: 2003, 89(9);1110-8 PubMed 12923046

Marc Sylva, Maurice J B van den Hoff, Antoon F M Moorman Development of the human heart. Am. J. Med. Genet. A: 2014, 164A(6);1347-71 PubMed 23633400"

Finally, there is a great variety of reputable sources of information. The only thing that needs changing is that the reference list should be revised. Some were left as a link and the list were inconsistent with its reference format.

---

This wikipage had all the sections required for this assignment and the team was very detailed in their content. There was also a good amount of referencing. However for certain areas, the entire reference was there instead of just the number. Also, the student numbers should be removed from the page. There was also a good number of photos used and it was good that they had a mix between self-drawn images and images obtained online. However, a way that could improve the images would be to add a description or a caption under each figure so it's easier to know what the picture is about. Some photos in this article lacked description, reference and copyright information, so that could be added as well. For most of the article, I can see that the team carried out a great amount of research for this topic, however it was a little difficult to understand some parts as they were very lengthy and slightly too content heavy. For the developmental timeline, the use of a table was good but the information could be presented in a more concise manner and the headings could be slightly more prominent to make it more readable. The signalling processes was also very well researched but quite lengthy, perhaps a few main signalling pathways could be chosen instead. For the abnormal developments, each abnormalities were well researched on. Perhaps images could be added to show the abnormalities and also maybe one or two more defects would be good. Overall, I think this group did a great job in researching and providing information on this wikipage. Maybe with a bit of tweaking here and there to make it more concise and readable, this wikipage would make a really good project.

User:Z5178462

2017-10-10T13:06:17Z

Z5178462: /* Peer Reviews */

[[Student Page]]

==Peer Reviews==

===Group 1- Cerebral Cortex===

Overall I find the information provided to be concise and easy to understand. The introduction was great in giving us a brief overview of page. The layout of the early development of the brain and the development of the cerebral cortex was really nice. I like the use of bullet points as this makes it easier to read. Also good amount of referencing is seen in this area. The use of the table is also a nice touch to the page and I like the picture used for E50-55. However, it could help to have another column with pictures for each row. That would help with the understanding of the text. For the anatomy of the cerebral cortex, it seems a little messy and hard to read as it is too point form. Perhaps these could be phrased into proper sentences with certain parts placed into bullet points to make it easier to read. Also, with the anatomy, pictures would be very helpful to aid in the explanation. For the functions of the cerebral cortex, it lists the functional areas but not the functions of those areas. Although it is stated in the video, which is a nice addition to the page, this could be improved by adding short sentences that state these functions that were mentioned as well. For Sections 1.4 and 1.5, references are also needed to state where the information was obtained from. The abnormalities section provides detailed explanations of the various disorders associated with the development of the cerebral cortex. There is also a good amount of pictures used. One thing I noticed was the references which was placed on the top of the section instead of throughout the text.

===Group 2- Kidney===

This wikipage is easy to read and the details provided was informative. The amount of text in each section was just nice and wasnt too overwhelming or insufficient, which was good. Overall, I noticed that the references could be improved. Instead of adding the link at the bottom, the team should use the code to reference such as in the section "Nephron development". Although the use of photos were really helpful and the choice of photos were great in the context they were added in, they were generally inconsistent in either description, reference or copyright information, which should be added to all photos. The anatomical position and kidney structure had clear and concise information and was easily understandable. The timeline of kidney embryology was really nice and I like how it was all 1-2 sentences long, making it really readable. In the section of developmental abnormalities, there is a large amount of text in the beginning that doesnt belong to any abnormality. Perhaps a subheading "Congenital Abnormalities of the Kidney and Urinary Tract" could be added to make it clearer as to what the text is about. Good use of image in each abnormalities though. The article appears to be unfinished but I'm assuming the team will be completing it after this peer review. To sum up, I like the readability of this wikipage and the images chosen, however, referencing and image descriptions could be further looked at for an even better page!

===Group 4- Eye===

Overall, this wikipage is pretty incomplete. However, that has been mentioned several times by the team, so i'm sure they will add on more after the peer review. The page is very neat and the text was quite concise. An introduction could be helpful to introduce what is an eye and what it does in the human body. In the anatomy of the adult eye, it was good that there were images of drawings to show the different parts of the eye, perhaps the drawings could be more clearly labelled with a thinner pen/pencil. Also a description of the image would be good as well. This section was well referenced. For the overview of eye develoment, I like the use of tables as it made it very easy to understand the content. The image (Figure 1.) was also well described and had appropriate copyright information. For the headings of this section, some could be changed such as 1.2 Eye Development, 1.2.1 Timeline of Eye Embryology, 1.2.4 Brief Outline/Description of the Eye Development. The portion on development of the eye components is incomplete, however for the parts that were there, there was not too much text and appropriate referencing. Pictures could be used in this section to improve it. For the congenital anomalies, I like the use of the table for ease of reading and understanding. Perhaps a more detailed description could be included. Also maybe the images could be added into the table as another column to make it neater. Good job so far, I think with some alterations and once they add the rest of the page, it would be a good wikipage! :)

===Group 6- Cerebellum===

Overall, this team's wikipage was really informative. They were detailed yet not too much information was given. There was a good balance with text and pictures. The pictures chosen were all of good quality as well with appropriate description, referencing and copyright information provided. The introduction was a very good brief of the entire page and explained what was to be expected. In the basic anatomy of the cerebellum, the subheadings were really well-defined. However, maybe neural development should be shifted to the developmental section instead. This section was well referenced. I like the use of the table to describe the cerebellum developmental weeks. The images used were really helpful in visualizing what was happening in those weeks. In the abnormalities section, it was short and concise with good picture. Maybe the caption of the photos could be placed together with the photo such as those in the table. This could make the photos look neater. Overall I find that this wikipage was well done, it had a good amount of text and photos and the references were all properly included.

 
{{2017ANAT2341 footer}}

Talk:2017 Group Project 6

2017-10-10T13:05:49Z

Z5178462: /* Peer Review */

{{ANAT2341Project2017discussion}}



=Project Starting Places=
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:15, 14 August 2017 (AEST) OK Group 6 below are some starting places.

{{Neural Links 2}}

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebellum+Development ''Cerebellum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebellum+Development ''Cerebellum Development'']

Cerebellum: links between development, developmental disorders and motor learning; [http://journal.frontiersin.org/article/10.3389/fnana.2012.00001/full]

Cellular commitment in the developing cerebellum [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290586/]

Recent papers

<pubmed limit=5>Cerebellum+Development</pubmed>

==Neural Development==
(z5114433)
will fix referencing stuff later #ceebsrn

Neural development is one of the earliest systems to begin and the last to be completed after birth due to its highly complex structure. The first step in neural development occurs at the end of week 3 and involves the folding of the neural tubes to form the cranial and caudal region of the embryo (''https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-26-embryonic-folding-and-flexion-of-the-embryo'') . There is a high chance of neural dysfunction and defects during the fetal neural development particularly due to the long development time frame and the need of certain nutrients such as folic acid to successfully close the tubes. Neural tube defects (NTDs) such as [[spina bifida]] and [[anencephaly]] can arise if the tubes do not close effectively.

=z5114433=
structure
time course
functional developing
what cells appear when

glial cells development

4th ventricle

Genes in abnormalities

pathway of development of cere cells
start of as neuroblast

=z5018156=
Things to remember:

Coordinates muscular activities - walking, crawling, writing

Embryo doesnt need the musuclar activities

Prenatal - neurons develop to carry out those activities later on

Postnatal - wiring up

Neural tube

Comes from pontine flexure - 4th ventricle -- the cerebellum develops into this space

Lamination of the cerebellum

https://www.ncbi.nlm.nih.gov/pubmed/19732611

https://www.ncbi.nlm.nih.gov/pubmed/21380713

Development: z5018156 - https://www.ncbi.nlm.nih.gov/pubmed/21295689

=Z5076158=
==Week 7 Work==
What I could add: Paramotal cells, molecular layer, what cerebellum connects to, how they are remodeled postnatally Kahals research
https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-150-the-brainstem-metencephalon-fourth-vesicle-the-cerebellum - good reference
LARSONS HUMAN EMBRYOLOGY TEXTBOOK
The metencephalon gives rise to the pons and the cerebellum, the adjacent rhombic lips also contribute to the development of cerebellum. The pons functions to relay signals that link both the spinal cord and cerebral cortex with the cerebellum and the cerebellum is a centre for postural and balance control. Pontine nuclei relay information from cerebrum to the cerebellum.
The cerebellum is first recognized as a pair of thickened cerebellar plates or cerebellar primordia.
Adjacent rhombic lips gives rise to Cerebellar granule cells
Major portion of the cerebellum consists of a narrow median swelling called the vermis and this grows faster than the flocculonodular which were the primitive part of the cerebellum and therefore becomes the dominant portion of the mature cerebellum.
Folding:
Primary fissure deepens by end of third month and divides vermis and hemispheres into a cranial anterior lobe and caudal middle lobe. Lobes divide further into lobules due to development of transverse fissures. This fissure formation and foliation continues throughout embryonic, fetal and postnatal life and this is done to increase the surface area of the cerebellar cortex.
2 types of grey matter present:
- Internal deep cerebellar nucler
- External cerebellar cortex
4 deep nuclei and all output of the cerebellar cortex is relayed through these nuclei.
These nuclei and cortex are produced by a process called neurogenesis and neuronal migration
1. Dentate
2. Globose
3. Emboliform
4. Fastigular

4th month – germinal layers undergo cell division and this produces populations of cerebellar neurons.
• Ventricular layer – purkinje cells, golgi cells, basket cells, stellate cells
• Granule cells remaining from the cerebellar cortex (these arise from external germinal layer)
• External germinal layer – primitive nuclear neurons these migrate to form deep cerebellar nuclei
==Week 8 Work==
PAPER 1995
Cerebellum – about:
It consists of 3 layers with 2 principal classes of neurons
Granule cells studies of naturally occurring mutations and targeted gene disruption that block discrete steps in development of this region
Development of anterior portion of neural tube involves the formation of 3 brain vesicles:
1. Prosencephalon
2. Mesencephalon
3. Rhombencephalon
Division of rhombencephalon into metencephalic vesicles and myelincephalic vesicles (this forms in day 9)
Failure of neural tube closure creates gap along the dorsal aspect of the neural tube, which bows into a mouth-like structure as the tube bends to establish the pontine flexure.
Further deepening this newly formed pontine flexure, bringing the mesencephalon (midbrain) closer to the primordium of the cerebellum (metencephalon); anterior aspects of the myelincephalon (brainstem) fold underneath developing the cerebellum plate.

Cells fated for cerebellum are derived from both the mesencephalon and metencephalic vesicles (rhombencephalon). Neuroepithelium of the mesencephalon generated majority of the cells in the cerebellar cortex: V-like area of mediodorsal aspect of the anlarge arose from a caudal movement of cells from the mesencephalon.

PAPER 2014
Cerebellum has a very basic structure:
• Monolayer of inhibitory purkinje cells sandwiched between a dense layer of excitatory granule cells
• Subpiled molecular layer of granular cell axons and purkinje cell dendritic fibres
Granule cells receives inputs from outside the cerebellum and project to the purkinje cells, the majority of which then project to a variety of cerebellar nuclei in the white matter.
The area designated for the cerebellum to reside (anlage) during development was located between hindbrain and midbrain. Regulation of patterning in this early stage (E9) of development shows to be particularly important for development of the uniquely mammalian midline expanded region of the cerebellum, “vermis”.

Specific cell types are allocated along the dorsoventral axis. For glutamatergic cells of cerebellum, remarkably prolonged establishment and an important dynamic process that takes place at most dorsal interface between neural and non-neural roof plate tissue, the rhombic lip. This phase generates the basic dichotomy between GABAergic and glutamatergic cell types that underlies the conserved Purkinje-Granule cell circuit.
Cell type allocation proceeds a third, distinct temporal phase of development that extends into early prenatal (up to 2 years). In this phase, the principal derivative of the rhombic lip, the granule cell precursor, accumulates over the surface of the cerebellum and undergoes further rounds of symmetric division in a process of transit amplification that exponentially expands its numbers.
The anlage of the cerebellum is a product of mechanisms of segmentation that establish iterated rhombomeric subdivision within the hindbrain just after neural tube closure.
All cells of the cerebellum arise from dorsal rhomomere, a region definitively classified by absence of the expression of Otx and Hox genes. Majority of cerebellum arises from metencephalic (rostral) hindbrain.

=z5113034=
Vasculature of cerebellum originates from vertebral arteries and the arteries that arise from it.

Metencephalon; temporary structure that differentiates into pons and cerebellum ventrally and dorsally respectively.

Current Research

Key discoveries during research of cerebellar development

=Topic Selection=
Hi group! I am personally interested in the development of the heart! Also, are you guys happy to exchange details after the lab tomorrow? - z5018156

Hi! Im happy to share details! And yeah heart would be interesting, but I was also thinking maybe the ear? that could be cool

Hey, yeah I was thinking the heart- I did a course on it last semester, but i also feel its quite generic and the other groups would do something similar. Shall we wait until the end of prac and find each other? Call out number 6 LMAO (z5114433)

Hey all! I'm pretty open about topics but I was leaning towards the eye? Unless that's too close to optom, (and it might be a popular subject too?) I'm fine with anything. Let's find each other after prac! -z5113034

The ear sounds good as well as the eye, theres also the lungs as well! We can just make a list and then decide as a group! - z5018156

=Peer Review=
This page is very informative, well set-out, and easy to follow and read. The information is well-referenced and the images have the correct Copyright. The page would be improved by including a "Future Research Questions" section.

---

This page was easy to follow and had good flow, with relevant headings and subheadings relating to the development of the cerebellum. Basic anatomy of the cerebellum contained a good amount of information, which provided relevant background knowledge before jumping into the development. Images were nicely chosen and was very relevant to the content, and they were also cited properly. There were some sections under Anatomy of the cerebellum that were related to the development, so it would be better to move it into the "Development" section to further improve flow. The table of "Cerebellum Developmental Weeks" was very clever especially with the images used. There is a vast amount of references used, and they were done properly. A "Further questions" section is needed to address any research gaps as well as explore more information on the Cerebellum. So far, well done!

---

There is a good introduction into the cerebellum which is also connected to the page and what the page will explore. The “basic anatomy” subheading is nice and succinct with minimal text and clear diagrams that clearly represent the anatomy of the cerebellum. The “Vasculature” subheading also provides a good overview with a simple diagram to complement. The only thing I find a bit odd about all the subheadings under “basic anatomy” is that I feel as though we go from the adult human anatomy of the cerebellum into embryological anatomy of the cerebellum. I think it might serve you better to split these up or just rearrange/rename your subheadings a bit. The reason for this is because the cerebellum is quite complex so I think it would help to absorb the information.
The “cerebellum development” is a good and descriptive subheading with a good use of diagrams. Since there is quite a big chunk of text, it would probably be better if you broke it down where you could. So, for example, where you say: “there are two types of grey matter in the cerebellum…” you could easily use dot points. It just helps with readability.
The “cellular migration” subheading is very good and the diagram you found is a great representation of it. I like that you added images to complement each week of development in your first trimester timeline. If you can do the same for your second trimester timeline that would be great. Your “key historical discoveries” subheading could use some images (even if it is of the people who made the discoveries). You chose a good number of abnormalities to explore in that last section. You might want to add another section for “future questions” just to hint at what more we need to learn about cerebellum development. You have a solid, long list of references.

---

Really good project page. The page goes through almost everything required for the project. You need a section about Further Questions and Current Research. The project is really well written and easy to understand. There is a good introduction giving the reader an idea of what to expect from the project page and good use of pictures giving a basic understanding of the anatomy of the cerebellum. There is a lot of use of figures and tables, which makes it easier for the reader to understand the subject. Most of the figures have a figure number and text, this also makes it easier to get a quick view of what the text refers to. The layout of the page is also comfortable to go through, but I do think the title Cerebellum in blue is a bit disturbing. There is good use of references.

*It seems like you have mixed the context in '''Basic Anatomy of the Cerebellum section''' and the '''Cerebellum Development'''. During the 'Anatomy section, you start describing the developmental origin, which I think would fit better in the Developmental section.
*The first section in the '''Cerebellum Development''' has a lot of text. Maybe you can make some subsections to split of the text and makes it more comfortable to read.
*The '''Cerebellum Developmental weeks table''' is really good and has good use of pictures. But the format makes it really big. Maybe you can do this part in a different way, so it does not take that much space. For the table about the second trimester, it would be a good support for the reader to add pictures to this table too – like the first-trimester table.
*The '''Key Historical Discoveries''' has a lot of text. Maybe you can add some pictures or change the layout a bit.

---

Overall, this team's wikipage was really informative. They were detailed yet not too much information was given. There was a good balance with text and pictures. The pictures chosen were all of good quality as well with appropriate description, referencing and copyright information provided. The introduction was a very good brief of the entire page and explained what was to be expected. In the basic anatomy of the cerebellum, the subheadings were really well-defined. However, maybe neural development should be shifted to the developmental section instead. This section was well referenced. I like the use of the table to describe the cerebellum developmental weeks. The images used were really helpful in visualizing what was happening in those weeks. In the abnormalities section, it was short and concise with good picture. Maybe the caption of the photos could be placed together with the photo such as those in the table. This could make the photos look neater. Overall I find that this wikipage was well done, it had a good amount of text and photos and the references were all properly included.

---

Talk:2017 Group Project 4

2017-10-10T12:19:21Z

Z5178462: /* Peer Review */

{{ANAT2341Project2017discussion}}



== Group talk ==

=== To do ===

* An introduction of what the page will go through
* Make sure all the required subjects are in the project [[ANAT2341 Lab 1]]
* Glossary list
* Maybe add videos

=== Work sites ===

z5177670: Lens, Ciliary Body, Iris, Cornea (http://www.sciencedirect.com/science/article/pii/S1877117315000642, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1298807/pdf/taos00013-0203.pdf)

z5075778: Extraocular muscles and Retina

z5117343: Congenital Anomalies, Treatment, Diagnosis

z5075309: Cornea, Aqueous Chambers, Choroid and Sclera, Lacrimal Glands (<ref><pubmed>23528534</pubmed></ref >)

=== Timeline ===

I tried making a timeline of how I understand the events in eye development. Please add components or change in the timeline if you disagree - it's just a draft :-)

=== Eyes development===

'''Articles for general eye development'''

I found a few articles about the general eye development and thought I wanted to share them with you all. If we find some good references, please share it here on the page, so we can help each other :-)

https://www.ncbi.nlm.nih.gov/books/NBK10024/ - Development of the Vertebrate Eye

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504437/ - Eye Development and Retinogenesis

http://www.sciencedirect.com/science/article/pii/0014483575900755?via%3Dihub - The prenatal development of the human eye

https://www.ncbi.nlm.nih.gov/pubmed/10627820 - Lens development.

http://www.sciencedirect.com/science/article/pii/S0012160606014898?via%3Dihub - FGF-mediated induction of ciliary body tissue in the chick eye

http://dev.biologists.org/content/141/23/4432.long - The cellular and molecular mechanisms of vertebrate lens development

http://www.sciencedirect.com/science/article/pii/S0014483510000448 - On the growth and internal structure of the human lens

http://www.sciencedirect.com/science/article/pii/S1877117315000642 - Chapter Four - Corneal Development: Different Cells from a Common Progenitor

http://www.annualreviews.org/doi/full/10.1146/annurev.cellbio.17.1.255?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed (Need permission for this article)

http://onlinelibrary.wiley.com.wwwproxy1.library.unsw.edu.au/doi/10.1002/ajmg.a.35713/full

https://www.aao.org/eye-health/diseases/what-is-coloboma

http://jmg.bmj.com/content/jmedgenet/41/12/881.full.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126628/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581554/

https://www.ncbi.nlm.nih.gov/pubmed/11826019/

==Suggested Starting Places==
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:15, 14 August 2017 (AEST) OK Group 4 below are some starting places.

{{Vision Links}}

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Eye+Development ''Eye Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Vision+Development ''Vision Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Eye+Development ''Eye Development'']

Recent papers

<pubmed limit=5>Eye+Development</pubmed>

<references/>
=Peer Review=

This is a well structured page, that approaches the eye from the basics. I like that the anatomy and underlying physiology of the eye is established before the developmental processes. Overview is brief and to the point, and the Embryonic Contributions table is an important aspect. Iris development could be expanded on, and more journal article images could be included. The "Opac figure" file does not have the correct Copyright notice. On the whole this is a very good page.

---

The team should provide a brief description of what the images are on their page so readers will understand immediately what it is. The team could use some images to show Caregie Stages, but the section is yet to be completed. An explanation of the ‘Timeline of embryonic development’ table would be beneficial to help readers understand what the table is explaining. More resources could be used for the Anatomy of the Adult Eye so that the team has shown to have used a variety of sources and have done plenty of research. There are incomplete sections. The team could include current research and animal models as extra subheadings.

Subheadings and content that have been used show a good understanding of the topic area. The team has used their own images to display their learning. The references have been correctly cited. The use of tables helps readers understand what the content is about, and is easy to follow for readers. Some of the images have been cited correctly; they have references, copyright statements and the Student Image template. However, some of the images don’t have the Student Image template. The abnormalities subheading was done well with the use of images and references.

---

'''Peer review project 4:'''
* The project does not feel like it is finished. A lot of work still needs to be done, and some of the subheadings like retina, cornea, eyelids, lacrimal glands etc is still empty.
* I did not find any sections describing signalling, research or future questions and animal models. I miss some more research content and a research angle to the project.
* The few parts of the development of the eye components which has been written was good. It was easy to understand and had good referencing.
* In general, the project could use more pictures to support the text.
* The anatomy part of the project was good. The drawing made it easier to understand, even though the picture captions and numbers are missing. I did not have any difficulties understanding it and they wrote it in a very clear way.
* I liked the overview of the eye development, it made it clear what is happening when, which cells comes from which germ layer and the Carnegie stage is a nice adding, even though it is not finished.
* The abnormal development section is far from finished. I think it is an important part of the project and it would improve the project if the anomalies where describe more in depth and not in a table.
* The glossary section was empty as well.

---

Overall the project page looks good. I like that you have used a mix of student drawn diagrams and also paper derived ones. However, I do think that the ‘anterior eye’ drawing could be a little clearer, as it is a hard to tell what label corresponds to what. Also, the referencing for these I presume the original diagrams are from an anatomy book or something, this should be cited as a ‘based on…’
Stage 21 and 22 are missing and should be filled in with the accompanying information.
Having a number of tables really helps convey some of the information in a succinct manner, I particularly like this approach in the congenital abnormalities section.
In the ‘development of the eye components’ section some visual aids would be helpful otherwise there is just going to be a lot of text, and in order to keep the reader engaged, pictures or even animations would really help.
Could have a wider list of references, but I imagine as information is added so will these be.
Well done!

---

Has good structure, and overall a good feel in the developmental process of the eye. However the page seems to be unfinished, since there are a lot of blank areas under the subheadings (Retina, Cornea, Aqueous Chambers, Choroid and Sclera, Eyelids, Lacrimal Glands) and tables. Use of tables (i.e Carnegie stages) were very helpful and makes the content easier to understand. Hand drawn images were also very well done and aids in understanding the content, however they need to be labelled with "taken from ...". Congenital anomalies section lacks information, perhaps each anomaly deserves its own subheading since it is a quite important part of the topic. Although references were done correctly, a lot of parts seem to be missing citations ("Supporting Structures" and "Anterior Structure" under Anatomy). Overall, well done so far!

---

The page has an unfinished feel to it due to the lack of introduction, empty subheadings towards the end of the page and "this section is not done yet" written. Abnormalities is spelt incorrectly. Clever use of self drawn diagrams to avoid copyright issues, however I think it's better to use actual images from journals because some images are hard to understand, hard to read and don't look accurate- i was unaware the sclera, choroid and retina took up so much space in the vitreous humour. Id also advise to add images to show the developments of the embryonic eye, making it more appealing for the reader. Also adding images to the "Development of the eye components" section.

---

Firstly those pointers under the heading Eye Development need to be deleted; I think they're just suggestions from Mark but if not you already have the subheadings at the top? An introduction to the human eye might ease into the topic a little better. You have done the anatomy of the adult eye really really well. The images you've drawn yourself to outline the structure is really good and there is an abundance of information, so I think this part is great! The timelines need to be completed, as you've stated otherwise they would be good timelines to follow as a basic structure for someone learning about fetal eye development. The information in the short overview is really good, however overview of what exactly? Make the heading more specific. The development of the eye components is really good however isn't complete. This section could, however, be improved by adding some images in to show the region of the eye you're talking about. The abnormalities section is good, however, I think you could refer to the figure instead of just having them below and a little more information on the description or consequences of the diseases would add more substance. The glossary also needs to be completed. Your referencing seems to be correct throughout. Overall good work the page just needs a few changes and more information!

---

Reading through this page was very interesting and informative however I have a few points that could be adjusted to improve on your page. When inserting an image, adding a figure and brief description on the images would be useful. The timeline is good but there is no reference so it definitely needs one. When reading through all the other tables, references need to be used more as it isn't that easy to figure out what articles you have used to get your information. More work needs to be done to fill the headings under development of eye components and if more images were added it would be useful. Abnormalities could have a bit more of an explanation written as well. Your wiki page is looking good, I would suggest a heading on animal models would provide some good information and fit well with your page! I also haven’t read anything that tells us about signaling, this should have its own heading and should be explained quite well as it is an important part of development. With your figures, it would be nice if you referred to them throughout your text more, and integrated them with the headings. Although this page is a work in progress, the information written is useful and easy to understand.

---

This page jumps straight into the “anatomy of the adult eye”. However, I would suggest a brief introduction (just a paragraph) on the eye, its development, its function and what this page will explore. I think the text under the subheading “anatomy of the adult eye” could be cut down or at least altered. For example, you would be good to bold some words so that they stand out – especially if they are mentioned in the diagrams. The timeline is a very brief overview of development which is probably good considered you have a more detailed table for the Carnegie stages. I would suggest that you add another column for images for the Carnegies stages once you’ve completed it.
I think it’s good that you went into the specific development of the eye components but I think it would be more interesting if you added an image or diagram for each component. Also, you still need to complete the majority of the components in this section and when you do I would suggest you keep it at one to two paragraphs. The subheading, “Congenital anomalies”, is nice and succinct with the main anomalies outlined and images to visually represent each. However, I think here there is a bit of underrepresentation of the abnormalities. I feel like you could go into some more detail about each abnormality as other groups have done. The references could be extended to about 25 once you’ve filled in the empty parts.
You might also want to add a “current research” subheading as it is relevant and shows how our understanding and knowledge of the eye’s development is always expanding.

---

Overall the page looks neat in the arrangement of the information. Before the anatomy of the eye, maybe a short paragraph on the general information of the eye could be included to have a good introduction to the project page. For the anatomy of the eye, there is a fair amount of information and good images to support the information. If the group wants to take this section a little further, they could include histological images. For the images that were drawn, perhaps a brief description could be included. For the overview of the eye development, I really like how there was a general table foe the different weeks of development and then another following table with the carniage stages. This helped the reader to have a broad overview before narrowing down to the specifics. However, I think images re needed to understand the stages better because its hard to picture the development without any pictorial aid. Also, I think the headings and subheadings for this part may need to be modified. Maybe you can start off with “Development of the Eye”. and instead of “short overview”, you can change it to “An overview of Eye Development”. Also, all the information was taken from only one source so maybe more articles could be sourced in order to have more credibility.

For the development of the eye components, the content is sufficient and concise but more images are necessary as some parts gets a little confusing. There is a good amount of references for this section. For the congenital abnormalities, the table is a good way to present the information. However, more information about the abnormalities is needed under the description column. As for the images, I think maybe you could create another column and add the image to that row for each abnormality. This would give the table a more complete look and the section will be really good. There is also good amount of references and the images are correctly referenced and the copyright statements are included so that’s well done.

---

Overall, this wikipage is pretty incomplete. However, that has been mentioned several times by the team, so i'm sure they will add on more after the peer review. The page is very neat and the text was quite concise. An introduction could be helpful to introduce what is an eye and what it does in the human body. In the anatomy of the adult eye, it was good that there were images of drawings to show the different parts of the eye, perhaps the drawings could be more clearly labelled with a thinner pen/pencil. Also a description of the image would be good as well. This section was well referenced. For the overview of eye develoment, I like the use of tables as it made it very easy to understand the content. The image (Figure 1.) was also well described and had appropriate copyright information. For the headings of this section, some could be changed such as 1.2 Eye Development, 1.2.1 Timeline of Eye Embryology, 1.2.4 Brief Outline/Description of the Eye Development. The portion on development of the eye components is incomplete, however for the parts that were there, there was not too much text and appropriate referencing. Pictures could be used in this section to improve it. For the congenital anomalies, I like the use of the table for ease of reading and understanding. Perhaps a more detailed description could be included. Also maybe the images could be added into the table as another column to make it neater. Good job so far, I think with some alterations and once they add the rest of the page, it would be a good wikipage! :)

User:Z5178462

2017-10-10T12:18:41Z

Z5178462: /* Peer Reviews */

User:Z5178462

2017-10-10T11:31:53Z

Z5178462: /* Peer Reviews */

Talk:2017 Group Project 2

2017-10-10T11:30:31Z

Z5178462: /* Peer Reviews */

{{ANAT2341Project2017discussion}}



[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:15, 14 August 2017 (AEST) OK Group 2 below are some starting places.

{{Renal Links}}

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Renal+Development ''Renal Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Kidney+Development ''Kidney Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Renal+Development ''Renal Development'']

Recent papers

<pubmed limit=5>Renal+Development</pubmed>

Yay.

[[User:Z5178275|Z5178275]] ([[User talk:Z5178275|talk]]) 16:48, 10 August 2017 (AEST) I'm keen to do anything, but I think the brain is a little to complex for me. It also seems like a lot of other groups want to do that as well.

Cynthia here, I don't want to do the brain lol. I don't mind anything else though

[[User:Z5076039|Z5076039]] ([[User talk:Z5076039|talk]]) 17:03, 10 August 2017 (AEST)

==Peer Reviews==
This page is very informative and easy to read. I like the way it begins with the anatomy of the kidney in the developed human, and then progresses through its embryological development. The inclusion of developmental timeline table aids the flow of the page. Images are well integrated into the page with informative descriptions, however are not correctly referenced and do include the suitable Copyright statement. The page references well, but many sections are still unfinished. The page would benefit from a glossary at the end, and the "general info on the renal system" section should be included higher up on the page, or integrated into one of the other sections such as under the "kidney" heading. This page is very easy to read, but still needs some work.

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References should be cited correctly, i.e. don’t leave the links in the paragraphs and use proper citation. The images used should include references, copyright statements as well as the Student Image template required. If there are copyright images the team could be innovative and use their own diagrams to display structures. Use references for the ‘Timeline of Kidney Embryology’ to show that a variety of sources were used to complete the table. Current Research and Future Questions subheading is incomplete. Glossary of terms could be used to explain certain words, for example explaining in simple terms what GDNF and RET are.

Subheadings and content that have been used show a good understanding of the topic area. The team has bolded important words in relation to the kidney structure. The team has also placed a description under the images which allows readers to understand what the image is showing. The use of a table of ‘Timeline of Kidney’ allows readers to understand the content of the wikipage easily (maybe add images to the table). The team has shown comprehensive research; however, they need to show more referencing of sources to display the research that they have done.

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Overall this seems like a very well put together project and is very informative and easy to follow, and enjoyable to read. There is an appropriate balance of both text and visual diagrams, which greatly helped my understanding of the development of the kidneys. Figure 4 appears to be missing a reference. I do think perhaps an animation to explain nephron development may add additional clarity, and would provide another level of interaction for the reader. Perhaps also think about adding a student drawn diagram. The table is a great way to display the developmental stages in an easy to read manner.
The ‘blood supply’ section appears to be copy and paste which I assume will be rewritten? The section on current research is simply a list of PubMed links, and should be expanded to display content that is informative to the reader. Likewise, ‘questions for the future’ and ‘general info on the renal system’ remain as headings without any accompanying information. I think the questions for the future could be an interesting section, however general info I would think will have been covered elsewhere in the project.
The topic has clearly been researched well, and is well referenced, with most references being from scientific papers.
All in all I think this is a high quality project, that will only require a few additional tweaks to take it to the next level.

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The page flows very well and is easy to read. However, there is incorrect citing or no citing at all for images and texts which can trigger copyright issues, in some sections (mostly the beginning) of the page. The structure and anatomical position is extremely easy to read and comprehend, as well as the use of a table for development. Id advise to insert more images for development and the remaining sections to help the reader visualise the process instead of being overwhelmed by the information. Developmental abnormalities seem to contain information not necessarily needed. Maybe add the 5 paragraphs above "Kidney developmental abnormalities are diverse and they correspond to defects at different stages of kidney development" statement in a separate research topic. Good use of images for abnormalities though. Overall, the page is quite informative and has been researched effectively. It could be improved by slight tweaks in format aforementioned and correct referencing.

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I found the introduction to the kidney didn't flow very nicely and each sentence and paragraph were just points added in. Also, the grammar and punctuation in the introduction paragraph needs to be edited. The final thing that needs to be altered in the introduction paragraph is the links that have just been placed in. I'm not sure if they are the references but if so they need to be referenced correctly. The anatomical position and kidney structure are written really well! The only improvement I could make is with figure one and two reference them within the writing e.g. "Their inner structure can be divided into 2 main areas: the outer cortex, and the inner medulla, as illustrated in Figure 2", otherwise this section is really great. The timeline of the kidney embryology is good - basic outline which makes it easy to follow such a complex process. To make the page flow in a more succinct manner I think it would be good to put the kidney timeline under the kidney development heading instead of separating the two as the kidney development information expands on the timeline really well. The kidney development information is really good, and I think the images really complete it. However, the link at the end of nephrogenesis needs to be referenced correctly with intext. Also under blood supply, it says "THIS IS COPY AND PASTE" so I'm not sure if that's copied off another page or your own notes but that needs to be fixed. The abnormality section was really good and current research is a really interesting thing to include, that section just needs some more information which I'm sure you guys are already on top of! Overall its a really great page, good effort.

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I believe the headings chosen cover a sufficient amount of points you need in order to describe kidney development!
Referencing needs to be changed, its easy to use the code on the wiki cheat sheet and that automatically makes a reference for you!
When describing position, explain what retroperitoneal means, its not commonly known and also Thoracic 12 (T12) so people know what T12 refers too.
For images, you need to find the copyright information and reference them properly, Mark has step by step instructions on what needs to be included in the image description. There aren’t many references in the first section of the page, it would benefit if you included some. Under nephrogenesis, point 3, you can find the articles pubmed ID and add the reference in that way instead of manually doing it.
For developmental abnormalities, I feel like this could be explained better, it gets technical straight away and this can become quite confusing.
Current research and questions need to be worked on but I’m sure that’s whats intended.
Overall I think the content on this page is very relevant to kidney development and it was interesting to read. The two major things you should fix are image copyright and references and intext referencing.

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The introduction was a clear overview of the kidney, its main parts and its role. The connection to embryological development is great because it ties in with the rest of the page. The only note here is that the references need to be properly referenced, not just pasted with the link. The anatomical position and kidney structure parts were good because there wasn’t too much text and it only served to complement the diagrams. This is a good section to put before kidney embryology as we can understand what is developing as the embryo grows.
The timeline of kidney embryology was very brief. This is not bad considering you go into kidney development in more detail in the next section. However, I think another column for images would be worthwhile for the reader to visualise each stage or week of development.
Again, there are a few referencing errors that I’m sure you’ll rectify soon. There is a good use of references in nephron development. You’ve also clearly noted the copy and paste of the blood supply section. For this part, I would strongly recommend some diagrams because vasculature can be quite complicated to understand with just text.
The subheading, “Developmental abnormalities”, had a good chunk of research at the beginning that gave an overview of types of abnormalities before exploring three in detail. There was also a good amount of referencing. Clearly, the current research subheading is underdeveloped but there seems to be many articles that you will explore.
The reference list will be more reflective of your research once you fix some of those referencing errors.

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Good project page that goes through almost everything required for the page – the Current Research and Future questions section is lacking context though. The project is well written and easy to understand. Some sections have a better layout than others, so maybe you can work on making the same layout for the whole page. Some sections also have the wrong formatting of references, but other sections have perfect formatting. You must be careful with copy-pasting (Blood supply section) text into your project page without giving a reference from where you copy pasted the text from. Some of the pictures on the page also need more information on the image page itself like copyright information. It is good that you have added figure number to your pictures and a little description of it – this helps the reader to understand the context.

*'''The introduction''' to the Kidney is a really good, informative section. You need to change the format of your references in this section though. The layout might be a little bit confusing since there is a title “Kidney Structure” is in the middle of the page due to the pictures on each site.
*'''Nephron development and The developmental Abnormalities:''' These sections have a different layout compared to the earlier sections. It’s a lot of text, so try to make it look a bit more comfortable for the reader to go through. Maybe you can try to make the layout similar to some of the other sections and give the page a better flow.

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This page presents nicely and very easy to read. In the introduction section, instead of pasting those references, put them in pubmed reference properly so they can be put automatically into the references. They have introduced good and enough information on the anatomy of the kidney. It was not fully referenced in the kidney development section but it was well written in this section with informative pictures and figures. It could be easier to direct the text to its picture accordingly. The timeline would be more beneficial if pictures were included. Nice and shot subheadings. In the abnormalities section, brief paragraphs with well-referenced starting off nicely. Pictures and texts are presented fairly good and are easy to see without a mess, but some of the terms were hard to understand e.g."when the left and right kidneys fuse at their lower poles by a '''parenchymal isthmus''' located ventral to the abdominal aorta, forming a "U" shape", maybe have a glossary section at the end of the page. A lot of references in this section is a bonus indicating it was researched well. In the current research section, majority is a list of article links which I assume they are not yet touched on at this state, which is ok. But make sure to have 2-3 journal articles in this section. A few of future question along the way if you have any would be great. Overall, it is a nice written page, looking forward to see this as a whole!

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This wikipage is easy to read and the details provided was informative. The amount of text in each section was just nice and wasnt too overwhelming or insufficient, which was good. Overall, I noticed that the references could be improved. Instead of adding the link at the bottom, the team should use the code to reference such as in the section "Nephron development". Although the use of photos were really helpful and the choice of photos were great in the context they were added in, they were generally inconsistent in either description, reference or copyright information, which should be added to all photos. The anatomical position and kidney structure had clear and concise information and was easily understandable. The timeline of kidney embryology was really nice and I like how it was all 1-2 sentences long, making it really readable. In the section of developmental abnormalities, there is a large amount of text in the beginning that doesnt belong to any abnormality. Perhaps a subheading "Congenital Abnormalities of the Kidney and Urinary Tract" could be added to make it clearer as to what the text is about. Good use of image in each abnormalities though. The article appears to be unfinished but I'm assuming the team will be completing it after this peer review. To sum up, I like the readability of this wikipage and the images chosen, however, referencing and image descriptions could be further looked at for an even better page!

User:Z5178462

2017-10-10T10:35:38Z

Z5178462: /* Peer Review */

User:Z5178462

2017-10-10T10:35:27Z

Z5178462:

[[Student Page]]

==Peer Review==

===Group 1- Cerebral Cortex===

Overall I find the information provided to be concise and easy to understand. The introduction was great in giving us a brief overview of page. The layout of the early development of the brain and the development of the cerebral cortex was really nice. I like the use of bullet points as this makes it easier to read. Also good amount of referencing is seen in this area. The use of the table is also a nice touch to the page and I like the picture used for E50-55. However, it could help to have another column with pictures for each row. That would help with the understanding of the text. For the anatomy of the cerebral cortex, it seems a little messy and hard to read as it is too point form. Perhaps these could be phrased into proper sentences with certain parts placed into bullet points to make it easier to read. Also, with the anatomy, pictures would be very helpful to aid in the explanation. For the functions of the cerebral cortex, it lists the functional areas but not the functions of those areas. Although it is stated in the video, which is a nice addition to the page, this could be improved by adding short sentences that state these functions that were mentioned as well. For Sections 1.4 and 1.5, references are also needed to state where the information was obtained from. The abnormalities section provides detailed explanations of the various disorders associated with the development of the cerebral cortex. There is also a good amount of pictures used. One thing I noticed was the references which was placed on the top of the section instead of throughout the text.

 
{{2017ANAT2341 footer}}

User:Z5178462

2017-10-10T10:33:35Z

Z5178462:

[[Student Page]]

--Peer Review--

---*Group 1- Cerebral Cortex---

Overall I find the information provided to be concise and easy to understand. The introduction was great in giving us a brief overview of page. The layout of the early development of the brain and the development of the cerebral cortex was really nice. I like the use of bullet points as this makes it easier to read. Also good amount of referencing is seen in this area. The use of the table is also a nice touch to the page and I like the picture used for E50-55. However, it could help to have another column with pictures for each row. That would help with the understanding of the text. For the anatomy of the cerebral cortex, it seems a little messy and hard to read as it is too point form. Perhaps these could be phrased into proper sentences with certain parts placed into bullet points to make it easier to read. Also, with the anatomy, pictures would be very helpful to aid in the explanation. For the functions of the cerebral cortex, it lists the functional areas but not the functions of those areas. Although it is stated in the video, which is a nice addition to the page, this could be improved by adding short sentences that state these functions that were mentioned as well. For Sections 1.4 and 1.5, references are also needed to state where the information was obtained from. The abnormalities section provides detailed explanations of the various disorders associated with the development of the cerebral cortex. There is also a good amount of pictures used. One thing I noticed was the references which was placed on the top of the section instead of throughout the text.

 
{{2017ANAT2341 footer}}

User:Z5178462

2017-10-10T10:32:45Z

Z5178462:

{{ANAT2341ProjectGroup2017table}}

Here is the [[Student Page]] demonstration page I showed in the Practical class.

Use this page to practice editing and don't forget to add a topic to the [[2017 Group Project 5]] page.

[[Student Page]]

--Peer Review--

---*Group 1- Cerebral Cortex---

Overall I find the information provided to be concise and easy to understand. The introduction was great in giving us a brief overview of page. The layout of the early development of the brain and the development of the cerebral cortex was really nice. I like the use of bullet points as this makes it easier to read. Also good amount of referencing is seen in this area. The use of the table is also a nice touch to the page and I like the picture used for E50-55. However, it could help to have another column with pictures for each row. That would help with the understanding of the text. For the anatomy of the cerebral cortex, it seems a little messy and hard to read as it is too point form. Perhaps these could be phrased into proper sentences with certain parts placed into bullet points to make it easier to read. Also, with the anatomy, pictures would be very helpful to aid in the explanation. For the functions of the cerebral cortex, it lists the functional areas but not the functions of those areas. Although it is stated in the video, which is a nice addition to the page, this could be improved by adding short sentences that state these functions that were mentioned as well. For Sections 1.4 and 1.5, references are also needed to state where the information was obtained from. The abnormalities section provides detailed explanations of the various disorders associated with the development of the cerebral cortex. There is also a good amount of pictures used. One thing I noticed was the references which was placed on the top of the section instead of throughout the text.

 
{{2017ANAT2341 footer}}

Talk:2017 Group Project 1

2017-10-10T10:30:56Z

Z5178462: /* Peer Reviews */

{{ANAT2341Project2017discussion}}



=Cerebral Cortex=
==Introduction==
https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:37, 23 August 2017 (AEST)

==Lobes and Function==
4 Lobes: parietal, temporal, frontal, occipital
Video Overview: [https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and-physiology/nervous-system-introduction/v/cerebral-cortex "Cerebral Histology"]
[[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:32, 23 August 2017 (AEST)

==Neocortical Development==
Nature article: https://www.nature.com/nrn/journal/v9/n2/full/nrn2252.html [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

===6 Layers===
Layers I, II, III, IV, V, VI (see [http://www.ruf.rice.edu/~lngbrain/Sidhya/ "Cortical Layer Review"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

==Anatomy and Function==

to do:

-change from dot points

-add images

-references

-finish function information

===Cell Types===
http://www.ruf.rice.edu/~lngbrain/Sidhya/ [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

==Abnormalities==
PubMed Article: [https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ "Developmental Disorders"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:41, 23 August 2017 (AEST)

=Peer Reviews=

This page is very well structured and sequential. It provides a very detailed explanation of development under chronological subheadings. Subpages under images are well informed, but some images lack a proper Copyright phrase to indicate reproducibility. On the main page, some subheadings need to be capitalised (formatting) and student signatures need to be provided on relevant sections. The "Anatomy of the Cerebral Cortex" section is filled with dot points, and could be improved using Wiki formatting. The layout of the Abnormalities section could be improved, by changing the headings and subheadings. The page could benefit from a glossary list and 'Future Research' section. However, the reference list was well constructed. Overall the the page addresses the brief very well.

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Be careful in how the sentences are expressed for example in the introduction ‘the cerebral cortex is actually the outermost layer’; avoid using ‘actually’ in this sentence. Don’t forget to remove the student numbers from the posts. Minor grammatical errors; no use of commas in long sentences. The images do include copyright however the team has forgotten to place the Student Image Template that is required. The team should add a small description of the images that are on their webpage so readers will see immediately what the image is showing. The team could do a further questions subheading or an animal model subheading to explore more on the research of the Cerebral Cortex.

Subheadings and content that have been used show a good understanding of the topic area. The use of dot points where necessary are done well which makes the project easier to understand and read through. The use of tables to demonstrate the ‘Timeline of Corticogenesis’ is done comprehensively; maybe an image for each day that is explained should be added to show consistency (as only the last row has an image). The team has used their own diagrams which shows that the team was innovative in displaying their research. The references used are cited correctly, however, there are links at the bottom where they need to fix up and place it under references.

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Overall, the page is well structured and relatively easy to follow with the headings and subheadings relevant to the topic area (embryology of the cerebral cortex) The introduction was short and concise, which provided a relevant amount of background knowledge. Perhaps the anatomy and functions of the cerebral cortex could be put before the development so that it ties in with the introduction, however there is good amount of information under these subheadings. The images and videos were very relevant to the topic, which aided in understanding the content, however perhaps you could label them using "Figure 1", or "Table 1" etc as well as putting an appropriate description under the image/video. The use of the table on the "Timeline of Corticogenesis" as well as a good amount of dot points made it easier to understand and read through. The page is lacking a "further questions" section which would be quite informative in understanding the research gap to date. There are a good amount of references so far and they were done correctly. Well done.

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The page has good structure and formatting, however there is a significant unfinished touch. Anatomy of the Cerebral Cortex heading could place all the information in a table to make it easier to read as well as images to help the viewer visualise the process. Maybe remove the student numbers because they are unnecessary and make the page look not as professional. figures and tables need to be labelled as well as referencing and copyright claims. The diagram under the statement "Migration and division of all six layers of the cortex is completed during the third trimester. Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex." needs to be further explained because I had a hard time understanding the image and what each section meant. The video is a nice touch to help understand the function and placement of the cerebral cortex. Developmental abnormalities was well written, easy to understand and flowed nicely.

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The layout is looking very good, pictures could be a little smaller. I like the choice of headings, they explain well what is going to be talked about. I feel like you need to add headings like animal models and current research needs to be fixed but I’m sure that’s what is intended. I have some minor points for some of the headings:
Early development:
Spelling: Rhomboncephalon, and the instead of three at the beginning of a paragraph. Overall this heading was covered well
Development of cerebral cortex:
With images, you can add figure titles and this could make your page flow better!! Maybe expand a bit more on the key developmental zones in the human cortex, a brief explanation of what happens could help. The table is very well explained, however for E50-55 I can’t see a reference for all the information, also for the picture in the table for E50-55, you haven’t copied the copyright information so you should add that so it can be used in the page and also add the student template. I really like the drawn picture, but again a figure description would be helpful. This section is very well done.
Anatomy of the cerebral cortex
Some great points but needs to be broken up into paragraphs. Your Wikipedia link for the image is a good image however you should find the original, I recognize it from Cajal’s drawings so I think it could be in a paper about the cerebellum with Cajal. You have good ideas for this heading, also maybe add another image.
Functions of the cerebral cortex
For functional areas, I think a 2 sentence description of each area would be good and maybe a picture for reference.
Abnormalities
Intext referencing would be better. For images, add the student template to each!! Im not entirely sure how I feel about the youtube screenshots as images, maybe use one but try and find some in research articles aswell.
Overall, I think you’ve done a really good job at summarizing abnormalities.

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The introduction was a good opening to the Cortex page as it gives a brief overview and understanding of the cortex generally. The next subheading, “Early development of the Brain”, provides of a simple and clear explanation of the early development process however images would be a great addition to help visualise the text. Try having a look at some images that were shown to us in previous lectures on the brain development where it showed the neural plate, neuroectoderm and subsequent developments.
The next subheading, “Development of Cerebral Cortex”, would probably do better to be called “Later Development of Cerebral Cortex” as it would be a seamless flow from the previous subheading of “Early development…”. It was good that a labelled image was used and information was added for explanation. It helped orient me as I was going on to read about the timeline of corticogenesis. The timeline was detailed and the use of bold helped highlight key terms. However, I would suggest making another column for images on each day. Visual reinforcement just makes the information easier to absorb and make more sense.
The subheading, “Anatomy of the Cerebral Cortex”, is clearly in the editing process. I would just once again definitely recommend the use of images in this section, both hand-drawn diagrams and labelled images from the internet. I thought the use of a video was a clever way to cover the cerebral cortex functions. A bit of general text that briefly covers the functions of the main parts would be a good addition in this section, as a segue into the video.
The “Abnormalities” subheading was a good balance of text and images. It was easier to read because it was split into categories. I would only suggest that you mention at the beginning of the section that abnormalities associated with the cerebral cortex development can be divided into the following categories… I can see the references were placed at the beginning of the section and I’m assuming that is temporary. It is better if they are dispersed within the text where appropriate. There are a good bunch of references but you could probably aim for 25-30 for this page.

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This page needs some more information about current research, signaling processes, future questions and references to animal models. It would also be good with a table or quick overview of developmental origin. There has been a good use of pictures and tables. The setup of the section about abnormalities is really good. This page needs to use more references during the sections and not only at the start of a section. A glossary list would also be good for the reader to understand the page.

*'''Introduction''': Gives a quick knowledge of the cerebral cortex. A picture would be good to support this introduction and maybe a bit more description of the different terms. This section also needs references.
*'''Early Development:''' Good setup with bulleting. I find some of the context a bit confusing to read - especially these two sentences "From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five" and "During the fifth week, the embryonic brain undergoes rapid growth folding the neural tube and consequently resulting in three brain flexures" Maybe you can rephrase this.
*'''Development of Cerebral Cortex:''' Good section! Good overview.
*'''Timeline of Corticogenesis:''' Please give a short introduction of what Corticogenesis and Neurogenesis means. Good picture supporting the E50-55, maybe you can put this picture already in the section called "Key developmental zones in the human cortex" since this is the first time we get introduced to the different zones and plates and it would give a better basic knowledge before getting into Corticogenesis.
*'''Anatomy and Function of the Cerebral Cortex''': These two sections should maybe be earlier on the project page together with the introduction since it's a basic understanding of the Cerebral Cortex. Both sections look a bit messy, try to work on making it more simple and easier to read - it kind of looks like personal notes and not a proper information site :-) These sections also need some references. The video in this section gives a good understanding. Good idea putting a video on the page.
*'''Abnormalities associated with Cerebral Cortex Development:''' This section is really good. Great overview of the different scenarios and a lot of pictures to support the reading. Instead of mentioning all the references in the start of the section, you should add the specific reference used for each subsection, this will make it easier for the reader to look up references for specific sections.

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In the introduction section, it was not referenced where the information facts are from. This section should introduce a brief information on the topic, what you are going to discuss on the whole wiki page, introduce current researches and animal models to support the new findings and understandings. Also, don't use "actually" in the sentence.
On the page, It is better to write in full sentences instead of dot points as I've seen a lot of them and include any of scientific words in the glossary section at the end of the page. Where you've inserted picture, it will be clearer to also include it within the text in brackets for example (Figure 1).
Any figures or pictures on this page needs references as well.
In the abnormality section, it is well written with supporting pictures, but in my opinion, it is easier to read if the the figures/pictures are on the same side and texts on the other side instead of alternating. This section was very thoroughly referenced too. I think a small paragraph under the heading introducing the different type of disorders before going into greater details.
Don't focus too much on the anatomy as I can see this section is not finished nor written in paragraph and no pictures or figures, would be better to swap anatomy with some other embryology discussion for example, signalling processes.
Touch on current researches, animal model if any and future questions as they were not seen on the page. Also include a glossary table. References section is looking good but more is needed.

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Overall I find the information provided to be concise and easy to understand. The introduction was great in giving us a brief overview of page. The layout of the early development of the brain and the development of the cerebral cortex was really nice. I like the use of bullet points as this makes it easier to read. Also good amount of referencing is seen in this area. The use of the table is also a nice touch to the page and I like the picture used for E50-55. However, it could help to have another column with pictures for each row. That would help with the understanding of the text. For the anatomy of the cerebral cortex, it seems a little messy and hard to read as it is too point form. Perhaps these could be phrased into proper sentences with certain parts placed into bullet points to make it easier to read. Also, with the anatomy, pictures would be very helpful to aid in the explanation. For the functions of the cerebral cortex, it lists the functional areas but not the functions of those areas. Although it is stated in the video, which is a nice addition to the page, this could be improved by adding short sentences that state these functions that were mentioned as well. For Sections 1.4 and 1.5, references are also needed to state where the information was obtained from. The abnormalities section provides detailed explanations of the various disorders associated with the development of the cerebral cortex. There is also a good amount of pictures used. One thing I noticed was the references which was placed on the top of the section instead of throughout the text.

2017 Group Project 5

2017-10-04T16:20:07Z

Z5178462: /* CPAM (Congenital Pulmonary Airway Malformation) */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

[[File:CPAMXCT.jpg|350px|thumb|right|Chest radiography and contrast CT imaging of the lungs of a 36-year old woman diagnosed with CPAM.]]

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

Cystic fibrosis (CF) is a disease caused an extreme functional deficiency of the cystic fibrosis trans-membrane conductance regulator (CFTR) protein. It is found in high numbers in epithelial cells that line the cylindrical structures of tissue that often secrete fluids rich in mucus, such as the pancreas and the lungs. Out of all the tissues, the airways have one of the highest amount of CFTR. With the absence of functional CFTR in the lungs, there is defective chloride and bicarbonate secretion into the alveolar secretions. This causes the pH of the airway surface fluid to drop and also prevents secretion of mucus strands from glands. This results in a condition known as CF lung disease. <ref name="PMID25814049"><pubmed>25814049</pubmed></ref>

====Cystic Fibrosis Lung Disease====

This disease is identified by early colonisation and infection of the airways. Due to the acidic conditions of the CF airway surfaces, there is often a significant flaw in the baby's anti-bacterial defences. This leads to a very rapid onset of infection and the resulting inflammatory response is very critical.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> The usual culprits are Staphylococcus aureus and Pseusdomonas aeruginosa, which when mucoid, becomes the dominant pathogen that attacks CF lung tissues.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref> The chronic airway and systemic inflammation that occurs as a result would then lead to tissue destruction and respiratory failure.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> In fact, respiratory failure secondary to lung damage is the usually cause of death for CF patients with most of the damage caused arising from the inflammation instead of the actual bacteria.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref>

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-04T16:17:55Z

Z5178462: /* CPAM (Congenital Pulmonary Airway Malformation) */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

[[File:CPAMXCT.jpg|300px|thumb|right|Chest radiography and contrast CT imaging of the lungs of a 36-year old woman diagnosed with CPAM.]]

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

Cystic fibrosis (CF) is a disease caused an extreme functional deficiency of the cystic fibrosis trans-membrane conductance regulator (CFTR) protein. It is found in high numbers in epithelial cells that line the cylindrical structures of tissue that often secrete fluids rich in mucus, such as the pancreas and the lungs. Out of all the tissues, the airways have one of the highest amount of CFTR. With the absence of functional CFTR in the lungs, there is defective chloride and bicarbonate secretion into the alveolar secretions. This causes the pH of the airway surface fluid to drop and also prevents secretion of mucus strands from glands. This results in a condition known as CF lung disease. <ref name="PMID25814049"><pubmed>25814049</pubmed></ref>

====Cystic Fibrosis Lung Disease====

This disease is identified by early colonisation and infection of the airways. Due to the acidic conditions of the CF airway surfaces, there is often a significant flaw in the baby's anti-bacterial defences. This leads to a very rapid onset of infection and the resulting inflammatory response is very critical.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> The usual culprits are Staphylococcus aureus and Pseusdomonas aeruginosa, which when mucoid, becomes the dominant pathogen that attacks CF lung tissues.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref> The chronic airway and systemic inflammation that occurs as a result would then lead to tissue destruction and respiratory failure.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> In fact, respiratory failure secondary to lung damage is the usually cause of death for CF patients with most of the damage caused arising from the inflammation instead of the actual bacteria.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref>

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-04T16:16:51Z

Z5178462: /* Cystic Fibrosis */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

[[File:CPAMXCT.jpg|250px|thumb|right|Chest radiography and contrast CT imaging of the lungs of a 36-year old woman diagnosed with CPAM.]]

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

Cystic fibrosis (CF) is a disease caused an extreme functional deficiency of the cystic fibrosis trans-membrane conductance regulator (CFTR) protein. It is found in high numbers in epithelial cells that line the cylindrical structures of tissue that often secrete fluids rich in mucus, such as the pancreas and the lungs. Out of all the tissues, the airways have one of the highest amount of CFTR. With the absence of functional CFTR in the lungs, there is defective chloride and bicarbonate secretion into the alveolar secretions. This causes the pH of the airway surface fluid to drop and also prevents secretion of mucus strands from glands. This results in a condition known as CF lung disease. <ref name="PMID25814049"><pubmed>25814049</pubmed></ref>

====Cystic Fibrosis Lung Disease====

This disease is identified by early colonisation and infection of the airways. Due to the acidic conditions of the CF airway surfaces, there is often a significant flaw in the baby's anti-bacterial defences. This leads to a very rapid onset of infection and the resulting inflammatory response is very critical.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> The usual culprits are Staphylococcus aureus and Pseusdomonas aeruginosa, which when mucoid, becomes the dominant pathogen that attacks CF lung tissues.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref> The chronic airway and systemic inflammation that occurs as a result would then lead to tissue destruction and respiratory failure.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> In fact, respiratory failure secondary to lung damage is the usually cause of death for CF patients with most of the damage caused arising from the inflammation instead of the actual bacteria.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref>

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-04T16:16:05Z

Z5178462: /* Cystic Fibrosis */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

[[File:CPAMXCT.jpg|250px|thumb|right|Chest radiography and contrast CT imaging of the lungs of a 36-year old woman diagnosed with CPAM.]]

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

Cystic fibrosis (CF) is a disease caused an extreme functional deficiency of the cystic fibrosis trans-membrane conductance regulator (CFTR) protein. It is found in high numbers in epithelial cells that line the cylindrical structures of tissue that often secrete fluids rich in mucus, such as the pancreas and the lungs. Out of all the tissues, the airways have one of the highest amount of CFTR. With the absence of functional CFTR in the lungs, there is defective chloride and bicarbonate secretion into the alveolar secretions. This causes the pH of the airway surface fluid to drop and also prevents secretion of mucus strands from glands. This results in a condition known as CF lung disease. <ref name="PMID25814049"><pubmed>25814049</pubmed></ref>

====Cystic Fibrosis Lung Disease====

This disease is identified by early colonisation and infection of the airways. Due to the acidic conditions of the CF airway surfaces, there is often a significant flaw in the baby's anti-bacterial defences. This leads to a very rapid onset of infection and the resulting inflammatory response is very critical.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> The usual culprits are Staphylococcus aureus and Pseusdomonas aeruginosa, which when mucoid, becomes the dominant pathogen that attacks CF lung tissues.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref> The chronic airway and systemic inflammation that occurs as a result would then lead to tissue destruction and respiratory failure.<ref name="PMID25814049"><pubmed>25814049</pubmed></ref> In fact, respiratory failure secondary to lung damage is the usually cause of death for CF patients with most of the damage caused arising from the inflammation instead of the actual bacteria.<ref name="PMID26003065"><pubmed>26003065</pubmed></ref>

A millennial view of cystic fibrosis.: PMID: 26003065
Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy.: PMID: 25814049

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-04T15:45:41Z

Z5178462: /* CPAM (Congenital Pulmonary Airway Malformation) */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

[[File:CPAMXCT.jpg|250px|thumb|right|Chest radiography and contrast CT imaging of the lungs of a 36-year old woman diagnosed with CPAM.]]

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

A millennial view of cystic fibrosis.: PMID: 26003065
Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy.: PMID: 25814049

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-04T15:44:34Z

Z5178462: /* CPAM (Congenital Pulmonary Airway Malformation) */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

[[File:CPAMXCT.jpg|200px|thumb|center|Chest radiography and contrast CT imaging of the lungs of a 36-year old woman diagnosed with CPAM.]]

===Cystic Fibrosis===

A millennial view of cystic fibrosis.: PMID: 26003065
Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy.: PMID: 25814049

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-04T15:41:54Z

Z5178462: /* Newborn Respiratory Distress Syndrome */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

A millennial view of cystic fibrosis.: PMID: 26003065
Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy.: PMID: 25814049

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-04T15:40:54Z

Z5178462: /* Newborn Respiratory Distress Syndrome */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg|200px|thumb|right|An image of a chest radiography of a newborn with NRDS]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

A millennial view of cystic fibrosis.: PMID: 26003065
Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy.: PMID: 25814049

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-04T15:39:59Z

Z5178462: /* Newborn Respiratory Distress Syndrome */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg|200px|thumb|left|An image of a chest radiography of a foetus with NRDS]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

A millennial view of cystic fibrosis.: PMID: 26003065
Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy.: PMID: 25814049

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

File:CPAMXCT.jpg

2017-10-04T15:38:03Z

Z5178462: ==Congenital Pulmonary Airway Malformation== Diagnostic imaging of a 36-year old woman diagnosed with CPAM. On the left shows the chest radiography with the arrow pointing to the lobulated medial right upper lobe nodule. The photo on right shows a con...

File:CPAM-XrayCT.jpg

2017-10-04T15:25:50Z

Z5178462: An image showing a diagnostic imaging of a 36-year old woman diagnosed with CPAM.

An image showing a diagnostic imaging of a 36-year old woman diagnosed with CPAM.

2017 Group Project 5

2017-10-04T15:13:12Z

Z5178462: /* CPAM (Congenital Pulmonary Airway Malformation) */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg|300px]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

A millennial view of cystic fibrosis.: PMID: 26003065
Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy.: PMID: 25814049

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-04T15:12:34Z

Z5178462: /* CPAM (Congenital Pulmonary Airway Malformation) */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg|300px]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

Congenital Pulmonary Airway Malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental abnormality of the lower respiratory tract.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> It affects approximately 1 in 30,000 live births and is the most common lung lesion that is diagnosed at 18-20 weeks of gestation by prenatal screening.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref> CPAM is described as the absence of normal alveoli and extreme proliferation and cystic dilation of the terminal respiratory bronchioles. These cysts located in the bronchioles are often lined with different types of epithelial lining, such as ciliated, cuboidal or columnar cells. They lack normal structure and there is usually an absence of cartilage in the bronchioles.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> The appearance of these cysts are said to be a result of unusual airway patterning and branching during lung morphogenesis.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

There are 5 types of CPAM, with Type 3 being adenomatoid and Types 1, 2 and 4 being cystic.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> They are usually characterised in the following way.<ref name="PMID27070354"><pubmed>27070354</pubmed></ref>

*Type 0- Acinar dysplasia
*Type I- Multiple large cysts or a single dominate cyst
*Type II- Multiple evenly spaced (sponge-like appearance)
*Type III- Bulky firm mass (adenomatoid appearance)
*Type IV- Peripheral cyst type

Out of all, Type II CPAM is more commonly seen to be associated with other congenital defects.<ref name="PMID24715554"><pubmed>24715554</pubmed></ref> Most people who have CPAM are usually diagnosed in the perinatal period when they present with respiratory distress symptoms such as those seen in babies with NRDS.<ref name="PMCID4821328"><pubmed>PMC4821328</pubmed></ref> In rare cases, they go undiagnosed until adulthood where symptoms arise as seen in the image of the chest radiography of a 36-year old woman diagnosed with CPAM.

===Cystic Fibrosis===

A millennial view of cystic fibrosis.: PMID: 26003065
Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy.: PMID: 25814049

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-04T11:45:22Z

Z5178462: /* Cystic Fibrosis */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg|300px]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

A congenital pulmonary airway malformation is a rare disorder of the pulmonary airway and a hamartomatous mass of disorganized lung tissues with various degrees of cystic change (https://www.ncbi.nlm.nih.gov/pubmed/24715554)

CPAM is characterized by the lack of normal alveoli, an excessive proliferation and cystic dilatation of terminal respiratory bronchioles with various types of epithelial lining. Microscopically the cyst linings are composed of ciliated, cuboidal or columnar cells and those cysts have lack of normal architecture and are frequently devoid of cartilage. Type 2 CPAM that is associated with other congenital anomalies is seen more frequently than other types. (http://www.turkjpath.org/text.php3?doi=10.5146/tjpath.2013.01208)

Prenatal and Postnatal Management of Congenital Pulmonary Airway Malformation: PMID: 27070354
Congenital Pulmonary Airway Malformation Type 2: A Case Report with Review of the Literature.: PMID: 24715554
Congenital pulmonary airway malformation in a 36 year-old female: PMCID: PMC4821328

===Cystic Fibrosis===

A millennial view of cystic fibrosis.: PMID: 26003065
Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy.: PMID: 25814049

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-04T11:43:49Z

Z5178462: /* CPAM (Congenital Pulmonary Airway Malformation) */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

{| border='0px'

|-
| {{Gastrointestinal stage 13 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_13|Early embryo (stage 13)]]

This movie shows the early embryonic development of lungs.

| {{Gastrointestinal stage 22 movie}}
| [[Movie_-_Gastrointestinal_Tract_3D_stage_22|Late embryo (stage 22)]]

This movie shows the late embryonic development of lungs.

|-
|}

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg|300px]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

A congenital pulmonary airway malformation is a rare disorder of the pulmonary airway and a hamartomatous mass of disorganized lung tissues with various degrees of cystic change (https://www.ncbi.nlm.nih.gov/pubmed/24715554)

CPAM is characterized by the lack of normal alveoli, an excessive proliferation and cystic dilatation of terminal respiratory bronchioles with various types of epithelial lining. Microscopically the cyst linings are composed of ciliated, cuboidal or columnar cells and those cysts have lack of normal architecture and are frequently devoid of cartilage. Type 2 CPAM that is associated with other congenital anomalies is seen more frequently than other types. (http://www.turkjpath.org/text.php3?doi=10.5146/tjpath.2013.01208)

Prenatal and Postnatal Management of Congenital Pulmonary Airway Malformation: PMID: 27070354
Congenital Pulmonary Airway Malformation Type 2: A Case Report with Review of the Literature.: PMID: 24715554
Congenital pulmonary airway malformation in a 36 year-old female: PMCID: PMC4821328

===Cystic Fibrosis===

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-04T11:23:47Z

Z5178462: /* Newborn Respiratory Distress Syndrome */

{{ANAT2341Project2017header}}

=Lungs=

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

To understand lung embryology, we must first understand what a fully grown adult lung looks and functions like, anatomically and histologically.

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung. The larger right lung consists of 3 lobes (superior, middle & inferior) whereas the smaller left lung has 2 lobes (superior & inferior). The trachea splits into the left and right bronchi in the lungs. The bronchi are hollow tubes composed for hyaline cartilage and are lined with respiratory epithelium which is ciliated pseudostratified epithelium.

Each lung receives air through these primary bronchi. As these primary bronchi enter the lungs, they branch into smaller secondary bronchi which carry air to each lobe of the lungs.

The respiratory epithelium lining the bronchi contains cilia and goblet cells. The cilia act as hair-like projections and goblet cells secrete mucus to coat the lining of the bronchi. Cilia works to push mucus secreted by goblet cells out of the lungs. In this way, any bacteria or viruses that enter the lungs stick to the mucus and are expelled out of the respiratory tract.

The small bronchioles branch off from the tertiary bronchi. Bronchioles are made of elastin fibres and smooth muscle tissue. The bronchioles branch into even smaller terminal bronchioles. They are the smallest tubes in lungs and terminate at the alveoli. The terminal bronchioles are capable of dilating and contracting to control the amount of airflow to the alveoli.

===Lung Histology===

[[File:Lung histology.png]]

The diagram shows the histology of the lung.

The alveoli are the functional units of the lungs which allow for gas exchange to occur between air in the lungs and blood in the capillaries of the lungs. Alveoli occur in small clusters called alveolar sacs at the end of a terminal bronchiole. The walls of alveoli contain simple squamous epithelial cells called alveolar cells with type I and type II alveolar cells.

==Lung Cardiovasculature==

[[File:Lung vasculature.png]]

This diagram shows the connection between the heart and the lungs, showing the pulmonary arteries and veins in the lungs. The heart and lungs are interdependent in embryonic development. Since vascular development exists prior to respiratory development, the way cardiovasculature interacts with lung anatomy and functioning is extremely significant. <ref name="PMCID3641728"><pubmed>PMC3641728</pubmed></ref>

The main pulmonary artery begins in the right ventricle and divides into two branches: the right and left pulmonary arteries. These arteries are responsible for carrying deoxygenated blood to their respective lobes.

The pulmonary veins, however, carry oxygenated blood from the lungs to the rest of the body. There are four pulmonary veins.

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="1" align="center"
|-bgcolor="CEDFF2"
| width="100" |<center>'''Stage'''</center>
| width="350" |<center>'''Development''' </center>
| width="350" |<center>'''Historical Discoveries'''</center>
| width="200" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="45" | The first stage of fetal lung development is the embryonic stage where the first structural features of the lung can be seen. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>
| width="65" | [[File:Germ layers.jpg|thumb| Three main germ layers (ectoderm, endoderm and mesoderm and their role in different body structures <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref> ]] [[File:Early lung develop.jpg|thumb| Early lung development demonstrating lung buds and their growth into left and right lungs <ref> Schittny, J. C. (2017). Development of the lung. Cell and Tissue Research, 367(3), 427–444. http://doi.org/10.1007/s00441-016-2545-0 </ref>]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" |The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.
| width="65" | image

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |The canalicular stage is an important step in the development of the lung parenchymal cells. The formation of these cells as well as the vascularization and angiogenesis of surrounding structures is prominent in this stage. The beginning of the process producing surfactant in the lungs starts here but is more evidently seen in the Saccular stage. Additionally, there is differentiation of the specialised pulmonary epithelium into peripheral squamous cells and proximal cuboidal cells. <ref> Warburton, D., El-Hashash, A., Carraro, G., Tiozzo, C., Sala, F., Rogers, O., … Jesudason, E. (2010). Lung Organogenesis. Current Topics in Developmental Biology, 90, 73–158. http://doi.org/10.1016/S0070-2153(10)90003-3 </ref>
| width="65" |<center> history </center>
| width="65" | image

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |The Saccular stage shows a marked decrease in the interstitium, making way for growing peripheral airways or saccules. The widening of these saccules marks the regions of future gas exchange in the lung. Capilliaries surround these saccules to form a capillary bilayer in the intersaccular septa <ref> https://www.ncbi.nlm.nih.gov/pubmed/6370120 </ref>. Throughout this stage, Type I and Type II pneumocytes can be identified. Type II pneumocytes have lamellar bodies that contain surfactant; a phospholipoprotein which is essential for the inflation of the lungs and to prevent their collapse. It is important for the first breath of a newborn; the higher the number of lamellar bodies corresponds to increased stability in lung functioning at birth. <ref> http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf </ref>
| width="65" |<center> history </center>
| width="65" | image

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" | This is the final stage of lung development that stretches from late fetal to early childhood.
| width="65" |<center> history </center>
| width="65" |
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Movies==

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 is apart of the GATA family of transcription factors which comprises of a conserved zinc-finger motif which modulate gene expression by binding to A/TGATA/G sequence. Through in situ hybridization, it has been shown that GATA6 is important in visceral endoderm differentiation and expression in embryonic bronchial epithelium.

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg|300px]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

A congenital pulmonary airway malformation is a rare disorder of the pulmonary airway and a hamartomatous mass of disorganized lung tissues with various degrees of cystic change (https://www.ncbi.nlm.nih.gov/pubmed/24715554)

CPAM is characterized by the lack of normal alveoli, an excessive proliferation and cystic dilatation of terminal respiratory bronchioles with various types of epithelial lining. Microscopically the cyst linings are composed of ciliated, cuboidal or columnar cells and those cysts have lack of normal architecture and are frequently devoid of cartilage. Type 2 CPAM that is associated with other congenital anomalies is seen more frequently than other types. (http://www.turkjpath.org/text.php3?doi=10.5146/tjpath.2013.01208)

===Cystic Fibrosis===

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

File:NRDS.jpg

2017-10-04T10:01:32Z

Z5178462: /* Newborn Respiratory Distress Syndrome (NRDS) */

File:NRDS.jpg

2017-10-04T10:01:15Z

Z5178462: /* Newborn Respiratory Distress Syndrome (NRDS) */

==Newborn Respiratory Distress Syndrome (NRDS)==

NRDS is also known as Hyaline Membrane Disease or Surfactant deficiency.

The typical radiological features of Surfactant Deficiency are:
*Small volume lungs
*Homogenous "ground glass" opacity
*Air bronchograms

This image is taken after surfactant administration but still shows that the heart is completely concealed by the diffused, homogenous lung fields.

Original File Name:RDS_IPPV.jpg http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/CXR/RDS/RDS_IPPV.jpg

Image and Text: National Women's Health at Auckland City Hospital

===Reference===

http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/LungParenchyma.htm

© Crown copyright [2000-2005] Auckland District Health Board
Material featured on this site is subject to Crown copyright protection unless otherwise indicated. The Crown copyright protected material may be reproduced free of charge in any format or media without requiring specific permission.

This is subject to the material being reproduced accurately and not being used in a derogatory manner or in a misleading context. Where the material is being published or issued to others, the source and copyright status must be acknowledged.

The permission to reproduce Crown copyright protected material does not extend to any material on this site that is identified as being the copyright of a third party. Authorisation to reproduce such material must be obtained from the copyright holders concerned.

File:NRDS.jpg

2017-10-04T10:01:03Z

Z5178462: /* Newborn Respiratory Distress Syndrome (NRDS) */

==Newborn Respiratory Distress Syndrome (NRDS)==

NRDS is also known as Hyaline Membrane Disease or Surfactant deficiency.

The typical radiological features of Surfactant Deficiency are:
*Small volume lungs
*Homogenous "ground glass" opacity
*Air bronchograms

This image is taken after surfactant administration but still shows that the heart is completely concealed by the diffused, homogenous lung fields.

Original File Name:RDS_IPPV.jpg http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/CXR/RDS/RDS_IPPV.jpg

Image and Text: National Women's Health at Auckland City Hospital

===Reference===

http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/LungParenchyma.htm

© Crown copyright [2000-2005] Auckland District Health Board
Material featured on this site is subject to Crown copyright protection unless otherwise indicated. The Crown copyright protected material may be reproduced free of charge in any format or media without requiring specific permission.

This is subject to the material being reproduced accurately and not being used in a derogatory manner or in a misleading context. Where the material is being published or issued to others, the source and copyright status must be acknowledged.

The permission to reproduce Crown copyright protected material does not extend to any material on this site that is identified as being the copyright of a third party. Authorisation to reproduce such material must be obtained from the copyright holders concerned.

2017 Group Project 5

2017-10-01T18:38:07Z

Z5178462: /* Meconium Aspiration Syndrome */

{{ANAT2341Project2017header}}

=Lungs=
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:15, 14 September 2017 (AEST) OK Feedback
* Better progress than some (in specific sub-headings)
* Long list of sub-headings but only the first few topics populated.
* No reference sources on teh page or allocated to topics.
* Where is the research
* Glossary of words used here.

An introduction to the lungs...

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

Medina -

Draw diagram of lung anatomy and upload picture

===Lung Histology===

Medina -

Draw diagram of lung histology and upload picture

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Stage'''</center>
| width="600" |<center>'''Development''' </center>
| width="600" |<center>'''Historical Discoveries'''</center>
| width="600" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="65" | The Embryonic stage is the first stage of lung development. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" | The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |<center> about </center>
| width="65" |<center> history </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |<center> about </center>
| width="65" |<center> history </center>

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" |<center> about</center>
| width="65" |<center> history </center>
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Review and research articles==

==Movies==

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 - transcriptional factor

- visceral endoderm differentiation

- expressed in early development of bronchial epithelium

- required for regeneration of pulmonary epithelium

- Mouse model -->

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. <ref name="PMID26760414"><pubmed>26760414</pubmed></ref> Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg|300px]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris.<ref name="PMID26760414"><pubmed>27486480</pubmed></ref> It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs. <ref name="PMID25721501"><pubmed>25721501</pubmed></ref>

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth.<ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref> Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.<ref name="PMID26760414"><pubmed>26760414</pubmed></ref><ref name="PMCID2666857"><pubmed>PMC2666857</pubmed></ref>

===CPAM (Congenital Pulmonary Airway Malformation)===

A congenital pulmonary airway malformation is a rare disorder of the pulmonary airway and a hamartomatous mass of disorganized lung tissues with various degrees of cystic change (https://www.ncbi.nlm.nih.gov/pubmed/24715554)

CPAM is characterized by the lack of normal alveoli, an excessive proliferation and cystic dilatation of terminal respiratory bronchioles with various types of epithelial lining. Microscopically the cyst linings are composed of ciliated, cuboidal or columnar cells and those cysts have lack of normal architecture and are frequently devoid of cartilage. Type 2 CPAM that is associated with other congenital anomalies is seen more frequently than other types. (http://www.turkjpath.org/text.php3?doi=10.5146/tjpath.2013.01208)

===Cystic Fibrosis===

==Lung Cardiovasculature==

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-01T18:32:13Z

Z5178462: /* Meconium Aspiration Syndrome */

{{ANAT2341Project2017header}}

=Lungs=
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:15, 14 September 2017 (AEST) OK Feedback
* Better progress than some (in specific sub-headings)
* Long list of sub-headings but only the first few topics populated.
* No reference sources on teh page or allocated to topics.
* Where is the research
* Glossary of words used here.

An introduction to the lungs...

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

Medina -

Draw diagram of lung anatomy and upload picture

===Lung Histology===

Medina -

Draw diagram of lung histology and upload picture

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Stage'''</center>
| width="600" |<center>'''Development''' </center>
| width="600" |<center>'''Historical Discoveries'''</center>
| width="600" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="65" | The Embryonic stage is the first stage of lung development. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" | The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |<center> about </center>
| width="65" |<center> history </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |<center> about </center>
| width="65" |<center> history </center>

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" |<center> about</center>
| width="65" |<center> history </center>
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Review and research articles==

==Movies==

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 - transcriptional factor

- visceral endoderm differentiation

- expressed in early development of bronchial epithelium

- required for regeneration of pulmonary epithelium

- Mouse model -->

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. <ref name="PMID26760414"><pubmed>26760414</pubmed></ref> Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg|300px]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===
Meconium aspiration syndrome (MAS) occurs in about 1% of all deliveries and usually affects term and post-term newborns. Meconium is a mixture of various substances that arises from the gastrointestinal tract such as digestive juices, bile, mucus, and cellular debris. It is usually sterile but can result in inflammation, infection and pneumonia. Since meconium is usually hidden from the infant's immune system in the digestive tract, it is not recognised by the immune cells when aspirated into the lungs. Instead, with many endogenous signals from cellular debris in the meconium, these immune cells recognise them as "damaged self", resulting in inflammation in the lungs.

Meconium-induced inflammation is often made worst when bigger particles in the meconium cause partial or complete obstruction of the airways, resulting in severe respiratory failure. Symptoms of MAS are similar to that of NDRS with tachypnea, grunting and cyanosis at birth. Chest radiography often shows diffused bilateral fluffy densities as seen in the Image.

Meconium-stained amniotic fluid is present in approximately 10% to 15% of deliveries, although the incidence of meconium aspiration syndrome is only 1%. Because meconium excretion often represents fetal maturity, meconium aspiration syndrome occurs in term and post-term newborns. Meconium is a conglomeration of desquamated cells, bile pigments, pancreatic enzymes, and amniotic fluid. Although sterile, it can lead to bacterial infection, irritation, obstruction, and pneumonia.

Meconium aspiration syndrome presents at birth as marked tachypnea, grunting, retractions, and cyanosis. Examination may reveal a barrel-shaped chest, with rales and rhonchi heard on auscultation. Chest radiography may show bilateral fluffy densities with hyperinflation. Treatment includes N-CPAP and supplemental oxygen. Ventilator support may be needed in more severe cases.

Perineal neonatal suctioning for meconium does not prevent aspiration. If the infant is hypotonic at birth, intubation and meconium suctioning are advised. Vigorous infants receive expectant management. (http://www.aafp.org/afp/2015/1201/p994.html)

Meconium aspiration syndrome (MAS) has been defined by clinical criteria: (1) respiratory distress (tachypnoea, retractions or grunting) in a neonate born through meconium-stained amniotic fluid (MSAF); (2) a need for supplemental oxygen to maintain oxygen saturation of haemoglobin (SaO2) at 92% or more; (3) oxygen requirements starting during the first 2 h of life and lasting for at least 12 h and (4) absence of congenital malformations of the airway, lung or heart [1].

Meconium consists of numerous substances of host origin mainly derived from the digestive tract, including salivary, gastric, pancreatic and intestinal juices, mucus, bile, bile acids, cellular debris, lanugo hairs, fetal wax and blood. Notably, since meconium is located ‘extracorporeally', like the whole content of the gastrointestinal tract, its constituents are hidden and normally not recognized by the fetal immune system. Normally, meconium is sterile as the colon is inoculated with bacteria after delivery. This is important with respect to the view of meconium as a potential danger to the fetus, containing innumerable potentially endogenous signals that can be recognized as ‘damaged self' by the immune system.

25721501

MAS is characterized by a diffuse parenchymal and airway disease in which meconium-induced inflammation of the lung is complicated by the mechanical effects of particulate meconium causing partial or complete airway obstruction. This combination results in severe respiratory failure, often with pulmonary artery hypertension as well as air block syndromes

PMC2666857

===CPAM (Congenital Pulmonary Airway Malformation)===

A congenital pulmonary airway malformation is a rare disorder of the pulmonary airway and a hamartomatous mass of disorganized lung tissues with various degrees of cystic change (https://www.ncbi.nlm.nih.gov/pubmed/24715554)

CPAM is characterized by the lack of normal alveoli, an excessive proliferation and cystic dilatation of terminal respiratory bronchioles with various types of epithelial lining. Microscopically the cyst linings are composed of ciliated, cuboidal or columnar cells and those cysts have lack of normal architecture and are frequently devoid of cartilage. Type 2 CPAM that is associated with other congenital anomalies is seen more frequently than other types. (http://www.turkjpath.org/text.php3?doi=10.5146/tjpath.2013.01208)

===Cystic Fibrosis===

==Lung Cardiovasculature==

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-01T12:33:20Z

Z5178462: /* Bronchopulmonary dysplasia */

{{ANAT2341Project2017header}}

=Lungs=
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:15, 14 September 2017 (AEST) OK Feedback
* Better progress than some (in specific sub-headings)
* Long list of sub-headings but only the first few topics populated.
* No reference sources on teh page or allocated to topics.
* Where is the research
* Glossary of words used here.

An introduction to the lungs...

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

Medina -

Draw diagram of lung anatomy and upload picture

===Lung Histology===

Medina -

Draw diagram of lung histology and upload picture

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Stage'''</center>
| width="600" |<center>'''Development''' </center>
| width="600" |<center>'''Historical Discoveries'''</center>
| width="600" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="65" | The Embryonic stage is the first stage of lung development. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" | The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |<center> about </center>
| width="65" |<center> history </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |<center> about </center>
| width="65" |<center> history </center>

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" |<center> about</center>
| width="65" |<center> history </center>
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Review and research articles==

==Movies==

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 - transcriptional factor

- visceral endoderm differentiation

- expressed in early development of bronchial epithelium

- required for regeneration of pulmonary epithelium

- Mouse model -->

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. <ref name="PMID26760414"><pubmed>26760414</pubmed></ref> Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg|300px]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

===Meconium Aspiration Syndrome===

Meconium-stained amniotic fluid is present in approximately 10% to 15% of deliveries, although the incidence of meconium aspiration syndrome is only 1%. Because meconium excretion often represents fetal maturity, meconium aspiration syndrome occurs in term and post-term newborns. Meconium is a conglomeration of desquamated cells, bile pigments, pancreatic enzymes, and amniotic fluid. Although sterile, it can lead to bacterial infection, irritation, obstruction, and pneumonia.

Meconium aspiration syndrome presents at birth as marked tachypnea, grunting, retractions, and cyanosis. Examination may reveal a barrel-shaped chest, with rales and rhonchi heard on auscultation. Chest radiography may show bilateral fluffy densities with hyperinflation. Treatment includes N-CPAP and supplemental oxygen. Ventilator support may be needed in more severe cases.

Perineal neonatal suctioning for meconium does not prevent aspiration. If the infant is hypotonic at birth, intubation and meconium suctioning are advised. Vigorous infants receive expectant management. (http://www.aafp.org/afp/2015/1201/p994.html)

===CPAM (Congenital Pulmonary Airway Malformation)===

A congenital pulmonary airway malformation is a rare disorder of the pulmonary airway and a hamartomatous mass of disorganized lung tissues with various degrees of cystic change (https://www.ncbi.nlm.nih.gov/pubmed/24715554)

CPAM is characterized by the lack of normal alveoli, an excessive proliferation and cystic dilatation of terminal respiratory bronchioles with various types of epithelial lining. Microscopically the cyst linings are composed of ciliated, cuboidal or columnar cells and those cysts have lack of normal architecture and are frequently devoid of cartilage. Type 2 CPAM that is associated with other congenital anomalies is seen more frequently than other types. (http://www.turkjpath.org/text.php3?doi=10.5146/tjpath.2013.01208)

===Cystic Fibrosis===

==Lung Cardiovasculature==

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-10-01T12:31:38Z

Z5178462: /* Bronchopulmonary dysplasia */

{{ANAT2341Project2017header}}

=Lungs=
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:15, 14 September 2017 (AEST) OK Feedback
* Better progress than some (in specific sub-headings)
* Long list of sub-headings but only the first few topics populated.
* No reference sources on teh page or allocated to topics.
* Where is the research
* Glossary of words used here.

An introduction to the lungs...

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

Medina -

Draw diagram of lung anatomy and upload picture

===Lung Histology===

Medina -

Draw diagram of lung histology and upload picture

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Stage'''</center>
| width="600" |<center>'''Development''' </center>
| width="600" |<center>'''Historical Discoveries'''</center>
| width="600" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="65" | The Embryonic stage is the first stage of lung development. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" | The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |<center> about </center>
| width="65" |<center> history </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |<center> about </center>
| width="65" |<center> history </center>

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" |<center> about</center>
| width="65" |<center> history </center>
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Review and research articles==

==Movies==

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 - transcriptional factor

- visceral endoderm differentiation

- expressed in early development of bronchial epithelium

- required for regeneration of pulmonary epithelium

- Mouse model -->

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. <ref name="PMID26760414"><pubmed>26760414</pubmed></ref> Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg|300px]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

Bronchopulmoary dysplasia (BPD) is described as a chronic lung condition derived from the disruption of normal pulmonary vascular and alveolar growth in infants born less than 28 weeks' gestation.<ref name="PMID24666156"><pubmed>24666156</pubmed></ref> Initially, BPD was said to be caused by treatment of NDRS by using mechanical ventilation. This ventilation was used to provide oxygen to infants who could not breathe on their own. However, a variety of factors from ventilation, such as infection, inflammation and oxygen toxicity, could stunt the postnatal maturation of the lungs, resulting in blunted alveolarization and dysmorphic pulmonary vasculature.<ref name="PMID26361876"><pubmed>26361876</pubmed></ref> In recent times, antenatal and perinatal factors that might disrupt lung development in extremely premature infants are also said to be the cause of BPD.<ref name="PMID4469359"><pubmed>4469359</pubmed></ref>

(BPD) was initially described almost 50 years ago as the chronic lung disease that developed when positive-pressure ventilation and oxygen therapy were used to treat “hyaline-membrane disease” or neonatal respiratory distress syndrome in preterm infants
Though BPD was once described as primarily due to postnatal injury from mechanical ventilation and oxygen therapy after preterm birth, it is increasingly appreciated that BPD results from antenatal and perinatal factors that interrupt lung development in infants born at the extremes of prematurity.
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469359/)

Perturbations to lung development result in lungs that are defective for gas exchange. This is exemplified in the clinical setting by bronchopulmonary dysplasia (BPD) (169, 218), a common complication of preterm birth originally described by Northway and coworkers in 1967 (258). Preterm infants with compromised respiratory function attributable to respiratory distress syndrome (RDS) require oxygen supplementation, often by mechanical ventilation. In these infants, infection, inflammation, oxygen toxicity, and volu- and baro-trauma from ventilation, together with other factors, stunt the postnatal maturation of the lung (154). This maturational stunting includes blunted alveolarization and the generation of a dysmorphic pulmonary vasculature, accompanied by aberrant pulmonary vascular wall remodeling, causing pulmonary hypertension (125). BPD is associated with significant morbidity and mortality in the neonatal intensive care unit, and survivors exhibit long-term consequences that persist into adulthood.
26361876

Bronchopulmonary dysplasia (BPD) is a chronic respiratory condition primarily affecting infants born less than 28 weeks gestational age. BPD and the diagnostic criteria that define it have evolved since the initial description of the disease more than four decades ago. BPD is one of the most common and serious complications of extreme premature birth. Despite advances in neonatal care and continued research into therapeutic strategies the incidence of BPD remains unchanged.

===Meconium Aspiration Syndrome===

Meconium-stained amniotic fluid is present in approximately 10% to 15% of deliveries, although the incidence of meconium aspiration syndrome is only 1%. Because meconium excretion often represents fetal maturity, meconium aspiration syndrome occurs in term and post-term newborns. Meconium is a conglomeration of desquamated cells, bile pigments, pancreatic enzymes, and amniotic fluid. Although sterile, it can lead to bacterial infection, irritation, obstruction, and pneumonia.

Meconium aspiration syndrome presents at birth as marked tachypnea, grunting, retractions, and cyanosis. Examination may reveal a barrel-shaped chest, with rales and rhonchi heard on auscultation. Chest radiography may show bilateral fluffy densities with hyperinflation. Treatment includes N-CPAP and supplemental oxygen. Ventilator support may be needed in more severe cases.

Perineal neonatal suctioning for meconium does not prevent aspiration. If the infant is hypotonic at birth, intubation and meconium suctioning are advised. Vigorous infants receive expectant management. (http://www.aafp.org/afp/2015/1201/p994.html)

===CPAM (Congenital Pulmonary Airway Malformation)===

A congenital pulmonary airway malformation is a rare disorder of the pulmonary airway and a hamartomatous mass of disorganized lung tissues with various degrees of cystic change (https://www.ncbi.nlm.nih.gov/pubmed/24715554)

CPAM is characterized by the lack of normal alveoli, an excessive proliferation and cystic dilatation of terminal respiratory bronchioles with various types of epithelial lining. Microscopically the cyst linings are composed of ciliated, cuboidal or columnar cells and those cysts have lack of normal architecture and are frequently devoid of cartilage. Type 2 CPAM that is associated with other congenital anomalies is seen more frequently than other types. (http://www.turkjpath.org/text.php3?doi=10.5146/tjpath.2013.01208)

===Cystic Fibrosis===

==Lung Cardiovasculature==

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-09-30T18:38:50Z

Z5178462: /* Newborn Respiratory Distress Syndrome */

{{ANAT2341Project2017header}}

=Lungs=
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:15, 14 September 2017 (AEST) OK Feedback
* Better progress than some (in specific sub-headings)
* Long list of sub-headings but only the first few topics populated.
* No reference sources on teh page or allocated to topics.
* Where is the research
* Glossary of words used here.

An introduction to the lungs...

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

Medina -

Draw diagram of lung anatomy and upload picture

===Lung Histology===

Medina -

Draw diagram of lung histology and upload picture

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Stage'''</center>
| width="600" |<center>'''Development''' </center>
| width="600" |<center>'''Historical Discoveries'''</center>
| width="600" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="65" | The Embryonic stage is the first stage of lung development. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" | The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |<center> about </center>
| width="65" |<center> history </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |<center> about </center>
| width="65" |<center> history </center>

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" |<center> about</center>
| width="65" |<center> history </center>
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Review and research articles==

==Movies==

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 - transcriptional factor

- visceral endoderm differentiation

- expressed in early development of bronchial epithelium

- required for regeneration of pulmonary epithelium

- Mouse model -->

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. <ref name="PMID26760414"><pubmed>26760414</pubmed></ref> Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg|300px]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

(BPD) was initially described almost 50 years ago as the chronic lung disease that developed when positive-pressure ventilation and oxygen therapy were used to treat “hyaline-membrane disease” or neonatal respiratory distress syndrome in preterm infants (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469359/)

===Meconium Aspiration Syndrome===

Meconium-stained amniotic fluid is present in approximately 10% to 15% of deliveries, although the incidence of meconium aspiration syndrome is only 1%. Because meconium excretion often represents fetal maturity, meconium aspiration syndrome occurs in term and post-term newborns. Meconium is a conglomeration of desquamated cells, bile pigments, pancreatic enzymes, and amniotic fluid. Although sterile, it can lead to bacterial infection, irritation, obstruction, and pneumonia.

Meconium aspiration syndrome presents at birth as marked tachypnea, grunting, retractions, and cyanosis. Examination may reveal a barrel-shaped chest, with rales and rhonchi heard on auscultation. Chest radiography may show bilateral fluffy densities with hyperinflation. Treatment includes N-CPAP and supplemental oxygen. Ventilator support may be needed in more severe cases.

Perineal neonatal suctioning for meconium does not prevent aspiration. If the infant is hypotonic at birth, intubation and meconium suctioning are advised. Vigorous infants receive expectant management. (http://www.aafp.org/afp/2015/1201/p994.html)

===CPAM (Congenital Pulmonary Airway Malformation)===

A congenital pulmonary airway malformation is a rare disorder of the pulmonary airway and a hamartomatous mass of disorganized lung tissues with various degrees of cystic change (https://www.ncbi.nlm.nih.gov/pubmed/24715554)

CPAM is characterized by the lack of normal alveoli, an excessive proliferation and cystic dilatation of terminal respiratory bronchioles with various types of epithelial lining. Microscopically the cyst linings are composed of ciliated, cuboidal or columnar cells and those cysts have lack of normal architecture and are frequently devoid of cartilage. Type 2 CPAM that is associated with other congenital anomalies is seen more frequently than other types. (http://www.turkjpath.org/text.php3?doi=10.5146/tjpath.2013.01208)

===Cystic Fibrosis===

==Lung Cardiovasculature==

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>

2017 Group Project 5

2017-09-30T18:37:28Z

Z5178462: /* Newborn Respiratory Distress Syndrome */

{{ANAT2341Project2017header}}

=Lungs=
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:15, 14 September 2017 (AEST) OK Feedback
* Better progress than some (in specific sub-headings)
* Long list of sub-headings but only the first few topics populated.
* No reference sources on teh page or allocated to topics.
* Where is the research
* Glossary of words used here.

An introduction to the lungs...

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

===Lung Anatomy===

Medina -

Draw diagram of lung anatomy and upload picture

===Lung Histology===

Medina -

Draw diagram of lung histology and upload picture

==Developmental origin overview==

A brief summary of the embryonic development of the lungs:<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone.</ref>

'''Day 22''' - Lung development begins. ''Respiratory diverticulum'' forms from the ventral outpouching of the endodermal foregut.

'''Day 26-28''' – Respiratory diverticulum undergoes bifurcation into right and ''left primary bronchial/lung buds''.

'''Weeks 5-28''' – Primary bronchial bugs undergo sixteen rounds of branching to generate the respiratory tree of the lungs. This produces ''secondary bronchial buds'', the ''lung lobes'', ''tertiary bronchial buds'', ''bronchopulmonary segments'' of the mature lung, ''terminal bronchioles'' and ''respiratory bronchioles''.

'''Week 36-Birth''' – Terminal branches of lungs are in a dense network of capillaries and are called ''terminal sac (primitive alveoli)''. They then begin to differentiate into mature alveoli which continue to form until 8 years old.

===Developmental timeline===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Stage'''</center>
| width="600" |<center>'''Development''' </center>
| width="600" |<center>'''Historical Discoveries'''</center>
| width="600" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Embryonic (weeks 4-5)'''</center>
| width="65" | The Embryonic stage is the first stage of lung development. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions.The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
| width="65" | Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. <ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/</ref>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Pseudoglandular (weeks 5-17)'''</center>
| width="65" | The Pseudoglandular stage of lung development is named after its histological appearance which is much like compound tubular glands. This is due to the dichotomous branching of conducting airways in the lung which is repeated up until the 16th week where they will be fully formed <ref>DiFiore, J., & Wilson, J. (1994). Lung Development. Seminars in pediatric surgery, 3(4), 221.</ref>. However, these branchings do not yet have functional alveoli; instead, specialised respiratory cells begin to develop. Crucially important to the branching of the airways is the presence of bronchial mesoderm as proven by Spooner & Wessells in 1970 (see history).
| width="65" | In 1970, an experiment by Spooner and Wessells demonstrated the need for the presence of surrounding bronchial mesoderm for adequate bronchial branching. <ref>
Spooner, B. S., & Wessells, N. K. (1970). Mammalian lung development: Interactions in primordium formation and bronchial morphogenesis. Journal of Experimental Zoology, 175(4), 445-454. doi:10.1002/jez.1401750404 </ref>. This was done through in vitro experiments with mice.
Additionally, In 1976 Masters published his work on the importance of epithelial-mesenchymal interactions during lung development. <ref>
Masters, J. R. W. (1976). Epithelial-mesenchymal interaction during lung development: The effect of mesenchymal mass. Developmental Biology, 51(1), 10. doi:https://doi.org/10.1016/0012-1606(76)90125-1</ref> This significance of this work is the discovery that the bronchial epithelium lining the primitive airways interacts with the mesenchyme, to then differentiate into specialised alveolar epithelium.

|-
| width="40" |<center>'''Canalicular (weeks 16-25)'''</center>
| width="65" |<center> about </center>
| width="65" |<center> history </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Saccular (weeks 24-40)'''</center>
| width="65" |<center> about </center>
| width="65" |<center> history </center>

|-
| width="40" |<center>'''Alveolar (week 36-8 years)'''</center>
| width="65" |<center> about</center>
| width="65" |<center> history </center>
|}

==Structure of respiratory network==
Physiologically, the organ can be divided into two parts:

'''The Conducting system''' – consists of all tubular structures including the larynx, trachea and bronchi. (image)

'''The Functional unit''' – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

[[File:3D model of the air way tree.jpg|700px]]

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

===The Conducting System===
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail.
The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed as contributing the backbone of the respiratory tree, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored.
For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally.
FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree.
In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior.
The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process.
Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

[[File:Modes of Lung Branching.jpg]]

This image is a stylised representation of the modes of lung branching.
a) lateral branching, b) planar bifurcation, c) orthogonal bifurcation, d) trifurcation

[[File:Ja1.gif|400px]]

This image is a stylised typical developmental branching pattern over time in a lung bud.

==='''Alveolus:''' the functional unit===

The alveolus are small "sac-like structures" in which gas exchange occurs across. Within the alveolus there are two types of cells that line the sacs. These are type I and type II alveolar cells, these cells must differentiate in a process known as alveolar differentiation and are both crucial for gas exchange.

'''Type I:''' Type I cells are flat and cover more than 90% of the alveolar surface in which gases diffuse across.

'''Type II:''' Type II cells are cuboidal shaped and synthesise pulmonary surfactants that hydrate and prevent the alveolar collapsing into itself by reducing surface tension.

It was previously thought that alveolar type I cells arise from type II cells, however more recent studies suggest that they both arise from a bipotent progenitor. After birth, type I cells are derived from rare, self-renewing, mature, long-living alveolar type II cells, that produce slowly, gradually expanding the the clonal foci of alveolar renewal.

Alveolar differentiation occurs in the distal region of the developing airway tree. Studies have found that over development there is an increase in alveolar differentiation and a decrease in branching morphogenesis as well as alveolar differentiation expanded distally over time.

ECAD (a cell junction protein stain) staining showed that undifferentiated cells at the branch tips were clustered and cuboidal, whereas differentiated alveolar cells (type1 and type 2) were at the non-branch tips and were flat and isolated cuboidal cells. This study suggests that in late lung stages branching continues at the distal edge of the airway tree whilst leaving behind cells undergoing alveolar differentiation. A genetic factor involved in alveolar differentiation is expression of hyperactive ''Kras'', which expands the branching of lungs, however reducing the differentiation of alveolar cells and suppresses cell flattening, a hallmark of alveolar cells.

One study, suggested that mothers who are overweight when pregnant can potentially effect the fetus in terms of lung development and air breathing at birth. The study looked at sheep who over-nourished their young, and found that the after birth the lambs who had overweight mothers had a reduced capacity for surfactant production as well as altered transport mechanisms within cells. This research can assist with the diagnosing and preventing potentially detrimental conditions that can occur during pregnancy.

*Not complete more content to be added

==Developmental signalling processes==

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. '''Fibroblast Growth Factor (FGF10)''' - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. '''Sonic Hedgehog (SHH)''' - produced in the epithelium and is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. '''Sox9''' - promotes proper branching morphogenesis by balancing the proliferation and differentiation of epithelial tip progenitor cells, whilst regulating the extracellular matrix. It is expressed at the distal tips of branching epithelium and controls multiple aspects of lung branching.

4. '''Heparan Sulfate Glycosaminoglycans (HS-GAG)''' - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

During branching morphogenesis, the distal tips of the branching epithelium contain a distinct population of progenitor cells that give rise to all epithelial types in early lung development, but become developmentally restricted after embryonic day 16.5 in mice. Because this epithelium is highly proliferative population of cells, a balance between differentiation and proliferation must be maintained during lung development. After embryonic day 16.5, Sox9 is down-regulated as differentiation begins, with Sox9 being expressed in the highest concentration where two new buds will form, and lowest where the cleft forms.
Two core signalling proteins consist of FGF10 and SHH. FGF10 has been shown to induce outgrowth of lung buds. FGF10 and SHH also engage in a negative feedback loop, in that FGF10 signalling induces SHH expression in the epithelium. This expression of SHH causes a repression in FGF10 expression in the mesenchyme of the tissue.

[[File:Fgf signalling.jpg|450px]]

a) FGF10 is transcribed at high levels in the distal mesenchyme (grey area). FGF10 stimulates SHH expression in the epithelium (red), thus promoting proliferation and outgrowth shown by the green arrow. b) The epithelium and mesenchyme are shown in red and grey respectively, showing the outgrowth of mesenchyme after the signalling pathway between both FGF10 and SHH.

[[File:Branching.jpg]]

This image shows three spatial locations of where concentrations of FGF10 are expressed, in order to generate different branching modes c) elongation d) terminal bifurcation e) lateral budding. This model is used in modern research, outlining the development of the conducting system of the lung

A recent study found that the production of a biologically active form of SHH was decreased after a loss of HS-GAG in the epithelium, highlighting the crucial requirement of HS-GAG in SHH-producing epithelial cells to maintain SHH signalling activity in the event of lung morphogenesis.

The branching pattern and branching rate are sensitive to the changes in the mesoderm shape and volume.
The growth of the epithelial tree is likely to adapt to fill the available space in the mesenchyme.

==Current understandings and areas of research==
include any relevant articles

==Review and research articles==

==Movies==

==Animal models==

'''Mouse models'''

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Wnt.... Sox 2

'''1. Wnt7b/Fzd2'''

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway (noncanonical/calcium, canonical, noncanonical planar cell polarity). Canonical Wnt pathway has a signalling role in embryonic lung development and with the action of β-Catenin by trans-activating the LEF/TCF pathway, which advances epithelial proliferation, differentiation and tissue development. On the other hand, the noncanonical pathway has been suggested to be a modulator of epithelial cell shape and cytoskeletal structure. To examine the function of Fzd2, mouse models were developed by in attempt to delete the Fzd2 gene by crossing over Fzd2 flox/flox allele mice with Shh cre allele mice. In the embryonic chimeric mice, at day 12.5, expression of Fzd2 was absent and by day 14.5 large cysts were observed in the distal lung region. It was also noted that in Fzd2 mutant mice, airways were shorter and wider and presence of planar bifurcation, leading to large cysts rather than distal branching. There were also molecular changes in signalling processes for lung branching morphogenesis involving the factors Fgf10, Bmp4, Fgfr2, and Shh. From the data, it is evident of Wnt7b/Fzd2's role in the modulation of lung epithelial cell shape and initiation of branch points.

'''2. Sox 2'''

Sox 2 - branching morphogenesis and epithelial cell differentiation.
- Sox 2 is a Sry related HMG
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

'''3. GATA6'''

GATA6 - transcriptional factor

- visceral endoderm differentiation

- expressed in early development of bronchial epithelium

- required for regeneration of pulmonary epithelium

- Mouse model -->

4. Gli2 & 3

==Abnormal development==

===Newborn Respiratory Distress Syndrome===

Newborn respiratory distress syndrome (NRDS) is usually seen in preterm infants that are born before 34 weeks' gestation. They usually present with respiratory distress symptoms such as tachypnea, grunting and cyanosis immediately after birth. A chest radiography would show a diffuse ground-glass appearance with air bronchograms and hypoexpansion. <ref name="PMID26760414"><pubmed>26760414</pubmed></ref> Usually, with treatment, infants with NDRS can recover wihout much long-term effects. In certain cases, bronchopulmonary dysplasia can occur and this will be talked about more in the next section.

[[File:NRDS.jpg thumb|Image of a chest radiology of a newborn with respiratory distress syndrome]]

====Hyaline Membrane Disease====

NRDS is often also called Hyaline Membrane Disease (HMD), as NRDS is usually due to a deficiency of pulmonary surfactant <ref name="PMID4984152"><pubmed>4984152</pubmed></ref> and the terminal bronchioles and alveolar ducts are seen to be lined with hyaline membranes. If surfactant is absent in infants, the alveoli would be more likely to collapse and this would explain most of the clinical features of NRDS. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

Prematurity is the most significant cause of the deficiency in surfactant. At around 23 weeks of gestation, surfactant is first seen in small amounts, and only at 30 weeks can surfactant in the lungs be easily detectable. Usually before 34 weeks' gestation, there is insufficient surfactant for the lungs to work properly. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Also, the mechanism to replace surfactant might be too immature in preterm babies so when surfactant is lost during breathing, there is a lack of production to replace it.<ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref> Another important cause is destruction of surfactant in the lungs by asphyxia before, during or after birth. This results in either the destruction of surfactant-producing alveolar cells or allow for the secretion of fibrinogen, which is known to inactivate surfactant. <ref name="PMCID1840752"><pubmed>PMC1840752</pubmed></ref>

===Bronchopulmonary dysplasia===

(BPD) was initially described almost 50 years ago as the chronic lung disease that developed when positive-pressure ventilation and oxygen therapy were used to treat “hyaline-membrane disease” or neonatal respiratory distress syndrome in preterm infants (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469359/)

===Meconium Aspiration Syndrome===

Meconium-stained amniotic fluid is present in approximately 10% to 15% of deliveries, although the incidence of meconium aspiration syndrome is only 1%. Because meconium excretion often represents fetal maturity, meconium aspiration syndrome occurs in term and post-term newborns. Meconium is a conglomeration of desquamated cells, bile pigments, pancreatic enzymes, and amniotic fluid. Although sterile, it can lead to bacterial infection, irritation, obstruction, and pneumonia.

Meconium aspiration syndrome presents at birth as marked tachypnea, grunting, retractions, and cyanosis. Examination may reveal a barrel-shaped chest, with rales and rhonchi heard on auscultation. Chest radiography may show bilateral fluffy densities with hyperinflation. Treatment includes N-CPAP and supplemental oxygen. Ventilator support may be needed in more severe cases.

Perineal neonatal suctioning for meconium does not prevent aspiration. If the infant is hypotonic at birth, intubation and meconium suctioning are advised. Vigorous infants receive expectant management. (http://www.aafp.org/afp/2015/1201/p994.html)

===CPAM (Congenital Pulmonary Airway Malformation)===

A congenital pulmonary airway malformation is a rare disorder of the pulmonary airway and a hamartomatous mass of disorganized lung tissues with various degrees of cystic change (https://www.ncbi.nlm.nih.gov/pubmed/24715554)

CPAM is characterized by the lack of normal alveoli, an excessive proliferation and cystic dilatation of terminal respiratory bronchioles with various types of epithelial lining. Microscopically the cyst linings are composed of ciliated, cuboidal or columnar cells and those cysts have lack of normal architecture and are frequently devoid of cartilage. Type 2 CPAM that is associated with other congenital anomalies is seen more frequently than other types. (http://www.turkjpath.org/text.php3?doi=10.5146/tjpath.2013.01208)

===Cystic Fibrosis===

==Lung Cardiovasculature==

==Future questions==

==Glossary==

==References==
<ref name="PMID24499815"><pubmed>24499815</pubmed></ref>
<ref name="PMC3787747"><pubmed>PMC3787747</pubmed></ref>
<ref name=”PMID25114215”><pubmed>25114215</pubmed></ref>
<ref name=”PMID18374910”><pubmed>18374910</pubmed></ref>
<ref name=”PMID11171334”><pubmed>11171334</pubmed></ref>
<ref name=”PMC3839746”><pubmed>PMC3839746</pubmed></ref>
<ref name=”PMID28759122”><pubmed>28759122</pubmed></ref>