Difference between revisions of "2014 Group Project 1"

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===Laryngeal Atresia===
 
===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>.
+
[[File:LaryngealAtresia.jpg|right|300px|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)===
 
===Congenital High Airway Obstruction Syndrome (CHAOS)===

Revision as of 12:23, 24 October 2014

2014 Student Projects
2014 Student Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7 | Group 8
The Group assessment for 2014 will be an online project on Fetal Development of a specific System.

This page is an undergraduate science embryology student and may contain inaccuracies in either description or acknowledgements.

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.

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.[1]

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.[2]

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

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. [3]


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. [4]

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.[5]


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.[6]


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.[7]

Development of the Respiratory Zone

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. [8]


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.[9]


ALVEOLAR DUCTS

File:4 subdivisons.jpg
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. [10]


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. [11]




Lung Development Stages

Stages Features
Embryonic (week 4-5)
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. [12]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.
Pseudoglandular (week 6-16) 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.[13]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. [8]
Canalicular (week 16 to 25) The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. [14]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. [15] The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.[8]
Saccular (week 24- 40) 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. [16]The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. [8]
Alveolar (week 36- 8 years of age) The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.[17]Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. [18]


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 [19]. However, physiologically, the organ can be divided into two parts that occur subsequently:

  1. The Conducting system- consisting of all the tubular structures such as the larynx, trachea, and bronchi.
  2. 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 [20].

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

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[21]:

a) Domain branching
Modes of branching: (a) lateral branching, (b) planar bifurcation, (c) orthogonal bifurcation and (d ) trifurcation
b) Planar bifurcation
c) Orthogonal bifurcation
d) Trifucation

• Another recent study conducted in 2013 [22], 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.

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


• A research group in 2011 [23], 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.
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

Lung Models Normal vs. Diseased.png

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 [24]. 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 [25].

Bailey282.jpg
Year Historic finding
400-300BC Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. [26]
1628 William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. [27]
1661
"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. [28] [27]
Early 1900s 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. [29]
1902 J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. [30]
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 [31]. 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 [32].
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 [33]. 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. [34]
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. [34]

3. 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 [35]. 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[36].

NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:[37]

  • Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development[35]
  • Maternal diabetes – high levels of insulin can delay surfactant synthesis[38]
  • Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity [38]
  • Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy [38]
  • Preterm Caesarean delivery – not allowing for lung maturation[39]
  • Genetic abnormalities that impair surfactant synthesis (ABCA3)[40]
  • Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid[41].

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. [41][42].

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. [43].

Problems associated with Meconium aspiration include[41]:

  • 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[44]. The complications can occur from a number of reasons following treatment[45]:

  • 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 [46].
  • 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)[47]. 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[48][49]. 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

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[50]. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) [51]. Genetic abnormalities have been identified as having an association with AL [52].

Congenital High Airway Obstruction Syndrome (CHAOS)

CHAOS.jpeg

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[53]. Reviews have revealed that most cases are fatal[54] but ex-utero partum treatments (EXIT) have been successful in treating this condition[55]

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. [56]

Congenital Pulmonary Airway Malformation

Laryngeal Atresia caused by Congenital High Airway Obstruction Syndrome

Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli[57]. 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[58]. 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. [59].

  • 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): [60].

  • Upper Azygos Lobe
  • Lower Azygos Lobe
  • the Lobe of the Azygos Vein

References

  1. 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
  2. Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/
  3. <pubmed>11936451</pubmed>
  4. 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
  5. <pubmed>11992723</pubmed>
  6. 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
  7. <pubmed>12107102</pubmed>
  8. 8.0 8.1 8.2 8.3 <pubmed>20692626</pubmed>
  9. 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
  10. 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
  11. <pubmed>8815817</pubmed>
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. <pubmed>24058167</pubmed>
  19. 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
  20. <pubmed></pubmed>24058167
  21. <pubmed>24004663</pubmed>
  22. <pubmed>24058167</pubmed>
  23. <pubmed>22359491</pubmed>
  24. <pubmed>23431607</pubmed>
  25. <pubmed>16601307</pubmed>
  26. <pubmed>5118050</pubmed>
  27. 27.0 27.1 <pubmed>1399659</pubmed>
  28. <pubmed>23377345</pubmed>
  29. <pubmed>19972530</pubmed>
  30. Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.
  31. <pubmed>18446178</pubmed>
  32. <pubmed>15985753</pubmed>
  33. <pubmed>14509914</pubmed>
  34. 34.0 34.1 <pubmed>24160653</pubmed>
  35. 35.0 35.1 <pubmed>20468585</pubmed>
  36. <pubmed>6071188</pubmed>
  37. <pubmed>10829971</pubmed>
  38. 38.0 38.1 38.2 <pubmed>20848797</pubmed> Cite error: Invalid <ref> tag; name "PMID20848797" defined multiple times with different content Cite error: Invalid <ref> tag; name "PMID20848797" defined multiple times with different content
  39. <pubmed>14629318</pubmed>
  40. <pubmed>15044640</pubmed>
  41. 41.0 41.1 41.2 <pubmed>10612363</pubmed>
  42. <pubmed>16651329</pubmed>
  43. <pubmed>19399004</pubmed>
  44. <pubmed>22785261</pubmed>
  45. <pubmed>19712501</pubmed>
  46. <pubmed>25031518</pubmed>
  47. <pubmed>24685676</pubmed>
  48. <pubmed>16928707</pubmed>
  49. <pubmed>22763554</pubmed>
  50. <pubmed>14325849</pubmed>
  51. <pubmed>2342705</pubmed>
  52. <pubmed>3566610</pubmed>
  53. <pubmed>22167132</pubmed>
  54. <pubmed>12778398</pubmed>
  55. <pubmed>9802816</pubmed>
  56. <pubmed>16798587</pubmed>
  57. <pubmed>24672262</pubmed>
  58. <pubmed>21355683</pubmed>
  59. <pubmed>21762550</pubmed>
  60. <pubmed>16333920</pubmed>

Glossary

occlusionBlockage or obstruction of a vessel