{{ANAT2341ProjectGroup2017table}}

==Peer assesments==
===Group 1 - Cerebral Cortex===
The introduction of this page gives a good general background but could benefit from adding bullet points to describe the six horizontal layers of the cortex and maybe a short summary of its clinical significance. 'Early Development' was well written, easy to follow and well referenced.
'Development of Cerebral Cortex' would benefit from a short introductory statement instead of going straight into the 'Main classes of neurons'. Pictures and tables in this section were informative and engaging to the reader. Hand-drawn picture was well done, colourful and easy to interpret.
'Anatomy of the Cerebral Cortex' looks unfinished and isn't easy to read as it doesn't flow or show a clear structure. No references can be seen and no pictures or tables to make for easier reading or understanding. The different layers of the cortex would greatly benefit from a table with structure/function format or a clear diagram. The same is true for 'Functions of the Cerebral Cortex'.
'Abnormalities associated with Cerebral Cortex Development' I liked the setup of this section because of its clear headings and subheadings as well as its informative pictures. The captions on some of these pictures need to be elaborated on. Also couldn't see any in text referencing which really needs to be present. Content is clear and concise and easy to follow. This section was engaging and well done.
'INFO/Research Links' was not finished yet but shows lots of research articles that could be promising.

=== Group 2 - Kidney ===
This page had a good general introduction to the kidneys and their function; the referencing needs to be fixed though. The pictures are helpful but do not have any copyright information or journal referencing which needs to be fixed ASAP.
'Timeline of Kidney Embryology' was very brief. 'Kidney Development' covered it in much more detail. Pictures used were well captioned and useful. Figure 4 in this section needs copyright information and proper citation. Figure 5 needs copyright information. 'Blood Supply' subheading has a 'THIS IS COPY AND PASTE' statement as the paragraph has been copied from a journal article but no reference has been made to said journal article.. I think this needs to be removed ASAP.
'Developmental abnormalities' is well written, referenced and has some bolded words which make it easier to interpret. Subheadings are clear and the pictures are informative.
'Current Research' has not yet been completed but several research articles are shown which is promising. 'Questions for the future' and 'General info on renal system' subheadings also need to be added to.
Overall, good start but would benefit from more content. Also each group page needs to have at least one hand-drawn diagram so this should be added.

===Group 3 - Heart===
'Introduction' is clear and informative, well referenced and gives a good outline for the rest of the page.
'Developmental Origin' has a bit of a confusing set up.. pictures are seemingly scattered and need captions. The 'Morphology of the Heart tube formation' hand-drawn figure is almost an exact replica of the original.. not sure if this is allowed because they are so similar.
'Developmental Timeline' has a very brief table.. would benefit from a better description of each week of development. This section has a couple of random references that should be at the bottom.
'Developmental Signalling Processes' diagrams need captions. There is a lot of information here which is very detailed.
'Current Research and Findings' has good subheadings and picture use; pictures need to have copyright information and citations added. Very detailed with good references throughought.
'Future Questions' needs to be added to but has shown evidence of initial research into this area.
'Glossary of terms' is a very good idea that has not yet been shown in other group topics. Maybe look into researching how to link certain words in the article to redirect to the bottom of the page to the Glossary of terms for quick definitions?
Some references also need to be properly cited in the 'References' section.
Over all, really well researched with some sections needing a bit more work.

===Group 4 - Eye Development===
This page could benefit from an introduction explaining the page and the overall importance of the eye and its development.
'Anatomy of the Adult Eye' has drawn pictures; whilst hand drawing is a great idea I believe these diagrams are a bit hard to understand as the eye is most easily displayed as a 3D model and these diagrams are all 2D. Otherwise, good content. Maybe a structure/function/location/diagram table would be good for this section?
'Overview of eye development' has a couple of sections that still need to be completed; also maybe a bit more detail to the events taking place at each stage would be beneficial.
'Development of the eye components' has good information but I feel that with all the separate parts to be completed there is going to be a lot of text here; again a table may be more useful or the use of pictures as it is getting a bit monotonous to read.
'Congenital Anomalies' this table is very brief and doesn't do each abnormality justice. Figures are useful.
This page has a fair bit of work to do; future research questions would be a good subtitle to have and glossary needs to be added to. Overall there is not much to read.

===Group 6 - Cerebellum===
'Basic Anatomy of the Cerebellum' has really useful and clear diagrams that support the content. However, the content was a bit brief in this section. All easy to read and follow.
'Early Brain Vesicles' has useful diagrams but needs more text to back them up.
'Cerebellum Development' is well written and referenced with appropriate diagrams and captions.
'Cerebellum Developmental Weeks' has very brief descriptions; needs to be more detailed and the pictures better explained or better captioned.
'Key Historical Discoveries' are interesting and well referenced. 'Ramon y Cajal' might need to be corrected to 'Ramon and Cajal' if reference is in Spanish.. Maybe add some pictures to this section too.
'Animal models' could use more subheadings and more examples of animals models as there is only currently one described.
'Abnormalities' has interesting pictures and examples but is a bit brief in its descriptions.
Overall, interesting topic and well used pictures. Some sections still need work; Glossary and maybe add a 'Future Research' topic to the page. Also a requirement of the project is to include one hand-drawn diagram which has not yet been added.

 
{{2017ANAT2341 footer}}

{| border="0"
|-bgcolor="CEDFF2"
| width="600" |<center>'''Year'''</center>
| width="600" |<center>'''Historical Development''' </center>

|-bgcolor="F5FAFF"
| width="40" |<center>[[Carnegie_stage_8|'''8''']]</center>
| width="65" |<center> 17 - 19</center>

|-bgcolor="F5FAFF"
| width="40" |<center>[[Carnegie_stage_10|'''10''']]</center>
| width="65" |<center> 22 - 23 </center>

|-bgcolor="F5FAFF"
| width="40" |<center>[[Carnegie_stage_12|'''12''']]</center>
| width="65" |<center> 26 - 30</center>

|-
| width="40" |<center>[[Carnegie_stage_13|'''13''']]</center>
| width="65" |<center> 28 - 32 </center>

User:Z5059373

2017-10-09T00:54:18Z

Z5059373:

{{ANAT2341ProjectGroup2017table}}

==Peer assesments==
===Group 1 - Cerebral Cortex===
The introduction of this page gives a good general background but could benefit from adding bullet points to describe the six horizontal layers of the cortex and maybe a short summary of its clinical significance. 'Early Development' was well written, easy to follow and well referenced.
'Development of Cerebral Cortex' would benefit from a short introductory statement instead of going straight into the 'Main classes of neurons'. Pictures and tables in this section were informative and engaging to the reader. Hand-drawn picture was well done, colourful and easy to interpret.
'Anatomy of the Cerebral Cortex' looks unfinished and isn't easy to read as it doesn't flow or show a clear structure. No references can be seen and no pictures or tables to make for easier reading or understanding. The different layers of the cortex would greatly benefit from a table with structure/function format or a clear diagram. The same is true for 'Functions of the Cerebral Cortex'.
'Abnormalities associated with Cerebral Cortex Development' I liked the setup of this section because of its clear headings and subheadings as well as its informative pictures. The captions on some of these pictures need to be elaborated on. Also couldn't see any in text referencing which really needs to be present. Content is clear and concise and easy to follow. This section was engaging and well done.
'INFO/Research Links' was not finished yet but shows lots of research articles that could be promising.

=== Group 2 - Kidney ===
This page had a good general introduction to the kidneys and their function; the referencing needs to be fixed though. The pictures are helpful but do not have any copyright information or journal referencing which needs to be fixed ASAP.
'Timeline of Kidney Embryology' was very brief. 'Kidney Development' covered it in much more detail. Pictures used were well captioned and useful. Figure 4 in this section needs copyright information and proper citation. Figure 5 needs copyright information. 'Blood Supply' subheading has a 'THIS IS COPY AND PASTE' statement as the paragraph has been copied from a journal article but no reference has been made to said journal article.. I think this needs to be removed ASAP.
'Developmental abnormalities' is well written, referenced and has some bolded words which make it easier to interpret. Subheadings are clear and the pictures are informative.
'Current Research' has not yet been completed but several research articles are shown which is promising. 'Questions for the future' and 'General info on renal system' subheadings also need to be added to.
Overall, good start but would benefit from more content. Also each group page needs to have at least one hand-drawn diagram so this should be added.

===Group 3===
'Introduction' is clear and informative, well referenced and gives a good outline for the rest of the page.
'Developmental Origin' has a bit of a confusing set up.. pictures are seemingly scattered and need captions. The 'Morphology of the Heart tube formation' hand-drawn figure is almost an exact replica of the original.. not sure if this is allowed because they are so similar.
'Developmental Timeline' has a very brief table.. would benefit from a better description of each week of development. This section has a couple of random references that should be at the bottom.
'Developmental Signalling Processes' diagrams need captions. There is a lot of information here which is very detailed.
'Current Research and Findings' has good subheadings and picture use; pictures need to have copyright information and citations added. Very detailed with good references throughought.
'Future Questions' needs to be added to but has shown evidence of initial research into this area.
'Glossary of terms' is a very good idea that has not yet been shown in other group topics. Maybe look into researching how to link certain words in the article to redirect to the bottom of the page to the Glossary of terms for quick definitions?
Some references also need to be properly cited in the 'References' section.
Over all, really well researched with some sections needing a bit more work.

===Group 4 - Eye Development===
This page could benefit from an introduction explaining the page and the overall importance of the eye and its development.
'Anatomy of the Adult Eye' has drawn pictures; whilst hand drawing is a great idea I believe these diagrams are a bit hard to understand as the eye is most easily displayed as a 3D model and these diagrams are all 2D. Otherwise, good content. Maybe a structure/function/location/diagram table would be good for this section?
'Overview of eye development' has a couple of sections that still need to be completed; also maybe a bit more detail to the events taking place at each stage would be beneficial.
'Development of the eye components' has good information but I feel that with all the separate parts to be completed there is going to be a lot of text here; again a table may be more useful or the use of pictures as it is getting a bit monotonous to read.
'Congenital Anomalies' this table is very brief and doesn't do each abnormality justice. Figures are useful.
This page has a fair bit of work to do; future research questions would be a good subtitle to have and glossary needs to be added to. Overall there is not much to read.

===Group 6 - Cerebellum===
'Basic Anatomy of the Cerebellum' has really useful and clear diagrams that support the content. However, the content was a bit brief in this section. All easy to read and follow.
'Early Brain Vesicles' has useful diagrams but needs more text to back them up.
'Cerebellum Development' is well written and referenced with appropriate diagrams and captions.
'Cerebellum Developmental Weeks' has very brief descriptions; needs to be more detailed and the pictures better explained or better captioned.
'Key Historical Discoveries' are interesting and well referenced. 'Ramon y Cajal' might need to be corrected to 'Ramon and Cajal' if reference is in Spanish.. Maybe add some pictures to this section too.
'Animal models' could use more subheadings and more examples of animals models as there is only currently one described.
'Abnormalities' has interesting pictures and examples but is a bit brief in its descriptions.
Overall, interesting topic and well used pictures. Some sections still need work; Glossary and maybe add a 'Future Research' topic to the page. Also a requirement of the project is to include one hand-drawn diagram which has not yet been added.

 
{{2017ANAT2341 footer}}

{| border="0"
|-bgcolor="CEDFF2"
| width="600" |<center>'''Year'''</center>
| width="600" |<center>'''Historical Development''' </center>

|-bgcolor="F5FAFF"
| width="40" |<center>[[Carnegie_stage_8|'''8''']]</center>
| width="65" |<center> 17 - 19</center>

|-bgcolor="F5FAFF"
| width="40" |<center>[[Carnegie_stage_10|'''10''']]</center>
| width="65" |<center> 22 - 23 </center>

|-bgcolor="F5FAFF"
| width="40" |<center>[[Carnegie_stage_12|'''12''']]</center>
| width="65" |<center> 26 - 30</center>

|-
| width="40" |<center>[[Carnegie_stage_13|'''13''']]</center>
| width="65" |<center> 28 - 32 </center>

2017-10-05T00:29:27Z

Z5059373:

2017 Group Project 5

2017-10-05T00:24:46Z

Z5059373: /* Developmental timeline */

{{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 which preceeds the formation of the air-blood tissue barrier. <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> 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>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>'''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.

==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

2017-10-05T00:23:05Z

Z5059373: /* Developmental timeline */

{{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" | [[File:Air blood barrier.gif|thumb| Change in pulmonary epithelium consequently leading to formation of the air-blood barrier in the developing lung <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>]]

|-
| 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> 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> 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" | 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.

==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>

File:Air blood barrier.gif

2017-10-05T00:19:24Z

Z5059373:

== Air-blood barrier formation in Canalicular stage of Human Lung Development ==
The formation of the air-blood barrier in the human lung is a crucially important functional step in its development. This diagram displays the change in specialised epithelium which consequently forms this air-blood barrier.

===Original Legend Text===
Formation of the air–blood barrier. During the early canalicular stage (a, rat lung) the epithelium of the terminal airways is still cuboidal and glycogen-rich (closed arrowhead). Already a bit more proximal, the epithelium begins to flatten out (open arrowhead) and starts to form the first optimized future air–blood barriers. During the latter process, the capillaries of the mesenchyme (closed arrow) “move” towards the epithelium (open arrow). In humans (b), remnants of the cuboidal epithelium (closed arrowhead) are still present at the uttermost periphery of the gas exchange region at postnatal day 26, even if alveolarization had already started approximately 6 weeks earlier. This finding illustrates the large overlap between different phases of lung development, especially if peripheral and central parts are compared. Light microscopical images, bar 50 μm. (From Woods and Schittny 2016, by courtesy of Cambridge University Press, New York) <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>

Image URL: https://static-content.springer.com/image/art%3A10.1007%2Fs00441-016-2545-0/MediaObjects/441_2016_2545_Fig4_HTML.gif

===Copyright===
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

===Reference===

2017-10-04T02:15:05Z

Z5059373: /* Developmental timeline */

{{ANAT2341Project2017header}}

=Lungs=

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

===Lung Anatomy===

[[File:Lunganatomy.png]]

This diagram shows the anatomy of the adult lung.

===Lung Histology===

[[File:Lung histology.png]]

==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.

Reference this - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641728/

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> ]]

|-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" | about https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340128/
| 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

==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===

==Future questions==

==Glossary==

==References==
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