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=Respiratory =

This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail.

==Historic findings==

Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.

[[File:Bailey282.jpg|center|500px]]

{|
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{| class="wikitable"
!align="center" valign="center"|Year
!align="center" valign="center"|Historic findings
|-
|align="center" valign="center"|400-300BC
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref>
|-
|align="center" valign="center"|1628
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref>
|-
|align="center" valign="center"|1661
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref>
|-
|align="center" valign="center"|Early 1900s
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref>
|-
|align="center" valign="center"|1902
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref>
|-
|align="center" valign="center"|1929
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.
|-
|align="center" valign="center"|1954
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.
|-
|align="center" valign="center"|1959
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.
|-
|align="center" valign="center"|1963
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref>
|-
|align="center" valign="center"|1994
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref>
|-
|}
|}

==Development of the Respiratory system Overview==

The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>

The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.

This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;
*Nose (including the nasal cavity)
*Mouth
*Larynx
*Trachea
*Bronchi and their branches

During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref>

The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.

=== Development of the Conducting Zone===

The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries.

ORAL CAVITY
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref>

LARYNX

The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]

TRACHEA

The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref>

BRONCHI

The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>

BRONCHIOLES

By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref>

=== Development of the Respiratory Zone===
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref>

TERMINAL BRONCHIOLES

Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>

ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]

The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>

ALVEOLI

The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref>

===Lung Development Stages===

{|
|-bgcolor="CEDFF2"
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{| class="wikitable"
!align="center" valign="center"|Stages
!align="center" valign="center"|Features
|-
|align="center" valign="center"|Embryonic (week 4-5)
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli.
|-
|align="center" valign="center"|Pseudoglandular (week 6-16)
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref>
|-
|align="center" valign="center"|Canalicular (week 16 to 25)
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref>
|-
|align="center" valign="center"|Saccular (week 24- 40)
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref>
|-
|align="center" valign="center"|Alveolar (week 36- 8 years of age)
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref>
|-
|}
|}

[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]

==Current Understandings and Areas of Research==

<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe>

Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:

# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi.
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes.

Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.

By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).

==1. '''The Conducting system''' - The respiratory network==

{|
|-bgcolor="lavenderblush"
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Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange.

• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:

:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,
(c) orthogonal bifurcation and (d ) trifurcation]]
:::b) Planar bifurcation
:::c) Orthogonal bifurcation
:::d) Trifucation
|}

{|
|-bgcolor="E0 FF FF"
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• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung.

[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]

|}

{|
|-bgcolor="CEDFF2"
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• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]

From their research they also conclude that the sequence of branching events may be the result of different growth speeds:

::::::::::::::Faster growth factors---> triggers lateral branching

::::::::::::::Slow growth factors----> bifurcated branching

|}

==2. '''The Functional Unit'''-Alveolus==

At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.

• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)

• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.

• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:

::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth.

::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.

However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.

==Current Models==

When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.

The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:

::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref>
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref>
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]
::• Ethical considerations
::• Cost effective

==Animal Models==

[[File:Lung Models Normal vs. Diseased.png|600px]]

3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]
Video explaining early respiratory development

==Abnormalities==
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates.

The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.

NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref>
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref>
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref>
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797
</pubmed></ref>
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref>
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref>
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref>
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.

===Meconium Aspiration Syndrome (MAS)===
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>.

Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways.
*Blockage of the airways

===Bronchopulmonary Dysplasia===
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:

*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.

===Cystic Fibrosis===
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function.

===Laryngeal Atresia===
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.

===Congenital High Airway Obstruction Syndrome (CHAOS)===
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref>

===Congenital Laryngeal Webs===
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref>

===Congenital Pulmonary Airway Malformation===
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.

*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes
*Type II – define by the presence of smaller more uniform cysts.
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.

===Azygos Lobe===
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.
*Upper Azygos Lobe
*Lower Azygos Lobe
*the Lobe of the Azygos Vein

==References==
<references/>

==Glossary==
'''occlusion'''Blockage or obstruction of a vessel

2014 Group Project 1

2014-10-23T23:40:45Z

Z3330991: /* Introduction */

{{ANAT2341Project2014header}}

=Respiratory =

==Introduction==

This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail.

=== Overview===

The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>

The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.

This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;
*Nose (including the nasal cavity)
*Mouth
*Larynx
*Trachea
*Bronchi and their branches

During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref>

The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.

=== Development of the Conducting Zone===

The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries.

ORAL CAVITY
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref>

LARYNX

The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]

TRACHEA

The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref>

BRONCHI

The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>

BRONCHIOLES

By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref>

=== Development of the Respiratory Zone===
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref>

TERMINAL BRONCHIOLES

Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>

ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]

The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>

ALVEOLI

The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref>

===Lung Development Stages===

{|
|-bgcolor="CEDFF2"
|
{| class="wikitable"
!align="center" valign="center"|Stages
!align="center" valign="center"|Features
|-
|align="center" valign="center"|Embryonic (week 4-5)
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli.
|-
|align="center" valign="center"|Pseudoglandular (week 6-16)
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref>
|-
|align="center" valign="center"|Canalicular (week 16 to 25)
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref>
|-
|align="center" valign="center"|Saccular (week 24- 40)
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref>
|-
|align="center" valign="center"|Alveolar (week 36- 8 years of age)
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref>
|-
|}
|}

[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]

==Current Research and Direction of Future Areas of Investigation==

<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe>

Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:

# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi.
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes.

Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.

By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).

{|
|-bgcolor="lavenderblush"
|

1. '''The Conducting system''' - The respiratory network

Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange.

• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:

:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,
(c) orthogonal bifurcation and (d ) trifurcation]]
:::b) Planar bifurcation
:::c) Orthogonal bifurcation
:::d) Trifucation
|}

{|
|-bgcolor="E0 FF FF"
|

• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung.

[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]

|}

{|
|-bgcolor="CEDFF2"
|

• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]

From their research they also conclude that the sequence of branching events may be the result of different growth speeds:

::::::::::::::Faster growth factors---> triggers lateral branching

::::::::::::::Slow growth factors----> bifurcated branching

|}

2. '''The Functional Unit'''-Alveolus

At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named alveolar differentiation.

• There are two alveolar cell types[2]:
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth.

:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.

==Current Models==

==Animal Models==

[[File:Lung Models Normal vs. Diseased.png|600px]]

==Historic findings==

Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.

[[File:Bailey282.jpg|center|500px]]

'''Surfactant'''

*1929: The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.

*1954: Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.

*1959: The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.

*1963: Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref>

*1994: Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref>

[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]

'''Alveoli formation'''

*An Italian scientist by the name of Marcello Malpighi (1628-1694) contributed greatly to medicine, particularly the understanding of anatomy as he was a pioneer biologist to utilise newly invented microscopes to closely observe. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref>

*Studies of the early 1900s specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref>

*J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref>

*The differentiation of surrounding mesenchyme into alveoli was contained within a membrane known as the pleural cavity that was separated off the peritoneal and pericardial cavities --> When was this distinction discovered..

1. Developmental Biology, 6th edition
By
Scott F Gilbert.
Swarthmore College
Sunderland (MA): Sinauer Associates; 2000.
ISBN-10: 0-87893-243-7
:'''Links:''' [http://www.ncbi.nlm.nih.gov/books/NBK9983/ | Developmental Biology]

Comparative embryology with detail on historical understandings of early respiratory development observed in various species. Accessible through PubMed.

2. Human Embryology and Morphology, 1902
By
Arthur Keith
London: Edward Arnold.
:'''Links:''' [http://php.med.unsw.edu.au/embryology/index.php?title=Book_-_Human_Embryology_and_Morphology_2 | Human Embryology and Morphology]

Historical images of past understandings on respiratory development

3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]
Video explaining early respiratory development

==Abnormalities==
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates.

The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.

NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref>
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref>
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref>
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797
</pubmed></ref>
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref>
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref>
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref>
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.

===Meconium Aspiration Syndrome (MAS)===
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>.

Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways.
*Blockage of the airways

===Bronchopulmonary Dysplasia===
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:

*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.

===Cystic Fibrosis===
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function.

===Laryngeal Atresia===
Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.

===Congenital High Airway Obstruction Syndrome (CHAOS)===
Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref>

===Congenital Laryngeal Webs===
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref>

===Congenital Pulmonary Airway Malformation===
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.

*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes
*Type II – define by the presence of smaller more uniform cysts.
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.

===Azygos Lobe===
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.
*Upper Azygos Lobe
*Lower Azygos Lobe
*the Lobe of the Azygos Vein

==References==
<references/>

==Glossary==
'''occlusion'''Blockage or obstruction of a vessel

2014-10-23T22:11:40Z

Z3330991: /* Notice */

==The larynx is develops from the 4th and 6th pharyngeal==

===Original Image reference ===

Original Image is adapted from: Figure 2 on the Development of the Larynx page.

Embryology of the respiratory system, accessed on the 20 September 2014, <http://embryology4genius.weebly.com/development-of-larynx.html>

===Notice===

This is a student hand drawn image and is is based upon Figure 2 on a website Embryology of the respiratory system: Development of larynx. The reference for this image are as above.

Beginning six months after publication, I (z3330991) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode."

{{Template:Student Image}}