Difference between revisions of "2014 Group Project 1"

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*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>  
 
*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|frame|Historical image of lung development|400px]]
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[[File:Lung_historical_image.PNG|frame|Historical image of lung development|200px]]
  
 
'''Alveoli formation'''
 
'''Alveoli formation'''

Revision as of 17:04, 6 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

http://onlinelibrary.wiley.com/doi/10.1046/j.1469-7580.2002.00097.x/full Airway and blood vessel interaction during lung development.]

A retinoic acid–dependent network in the foregut controls formation of the mouse lung primordium.

Lung epithelial branching program antagonizes alveolar differentiation.


The respiratory system allows the body to take in oxygen and exhale carbon dioxide through a process called breathing. the respiratory system moves the air in from the nose to the pharynx, larynx, trachea, bronchus and alveoli, which is where gas exchange occurs. During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that till about week 37 or birth is the fetal stage. However the respiratory system does not carry out gas exchange until birth. Whilst the embryo and fetus are in the mother, gas exchange occurs through the placenta. Once born the baby's lungs are drained and fill up with air automatically. The lungs do not inflate completely till about 2 weeks of the new born and the surfactant in each alveoli helps keep the lungs open and prevents it from collapsing.

the lung develops at week 4. the endoderm is he epithelium responsible for the development of the respiratory system. the splanchnic mesoderm developes into connective tissue, cartilage and muscle of the respiratory system.

Conducting zone

The conducting zone is made up nose to bronchioles and its 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 is where nasal cavity is lined with cilia, mucous membrane and consists of blood filled capillaries.

Oral Cavity

The first arch development from the pharyngeal arch is the substructure for the formation of the face,palate and oral cavity. To form the oral cavity the first arch must split into two portions; the maxillary and the mandibular. after 4 weeks of development these further divide into frontonasal process the 2 maxillary and 2 mandibular swellings. the neural crest cells, are abundant in these swellings as they are responsible for the growth of swellings. once these swellings fuse it forms the external face. there will be a small gap that becomes the mouth. [1]

The Stomodeum 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, separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. the membrane later breaks down and stomodeum opens into the pharynx forms the vestibule of oral cavity.

Pharynx


Larynx epithelium develops from endoderm of laryngotracheal tube. The splanchnic mesoderm is responsible for the connective tissue cartilage and muscle. however some of the cartilage develop from neural crest cells.

Bronchi Week 4 the lung bud develop and divides into two lung buds and each divides further. the left divides into two main bronchi and the right divides into three. these bronchis will ontinue to divide until there is about 17 subdividsions. Bronchiole


Respiratory zone The respiratory zone is where the oxygen and the carbon dioxide exchange with the blood. 10% of gas exchange is due to the alveolar ducts and the bronchioles, the other 90% is because of the alveoli.


Terminal Bronchioles

Alveolar ducts

Alveoli


"Birth" at birth the tracheal bification is at the leve of 4th thoracic verterbra. after birth there will be an additional 6 divisions in the bronchial tree.



5 stages of take place when the lungs develop;

Embryonic stage - week 4-5 Lung buds are formed from ventral wall of foregut where lobar division occurs.

Pseudoglandular stage - week 5-17 The conducting epithelium tubes surrounded by thick mesenchyme are formed, extensive airway branching. By two months there would have formed all of the segmental bronchi. At this stage the more distal structures are lined with cuboidal epithelium.

Canalicular stage - week 16-25 The bronchioles have formed and there is now an increase in capillary which are in contact with cuboidal epithelium and beginning of alveolar epithelium development. the lung morphology changes dramatically. the future air-blood tissue barrier is formed as a result of the differentiation of the pulmonary epithelium. the differentiation of the future conducting airways of the lung from the future gas exchange region is distinguishable.

Saccular stage - week 24-40 alveolar ducts and air sacs are developed and the terminal sac. the saccules widen and lengthen the airspac. the future gas exchange region expands dramatically. fibroblasts also differentiate , they produce extra matrix, collagen and elastin. Vascular tree and also grows in length and diameter during this time.

Alveolar stage- late fetal to 8 years of age the secondary septation occurs and there is a significant increase of number and size in capillaries and the alveolar. during the 1-3 years postnatally the alveoli continue to form increasing the gas exchange surface area.

Current Research, Models and Findings

Current Models

Current Reseach and Findings

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. 1. However, physiologically, the organ can be divided into two parts 2 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 [2].

By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see above for more information for the properties of this stage). 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 number 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[2].

• 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:

    1. Domain branching
    2. Planar bifurcation
    3. Orthogonal bifurcation
    4. Trifucation --add reference from intro

• Another recent study conducted in 2013[2], 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.

2. The Functional Unit

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


    1. 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.


References



<pubmed>24058167</pubmed> <pubmed>22844507</pubmed> <pubmed>20692626</pubmed> <pubmed>22359491</pubmed>


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 [1]. 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 [2].

Bailey282.jpg

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 [3]. 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 [4].
  • 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 [5]. 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. [6]
  • 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. [6]
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. [7]
  • 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. [8]
  • J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. [9]
  • 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..


References

  1. <pubmed>23431607</pubmed>
  2. <pubmed>16601307</pubmed>
  3. <pubmed>18446178</pubmed>
  4. <pubmed>15985753</pubmed>
  5. <pubmed>14509914</pubmed>
  6. 6.0 6.1 <pubmed>24160653</pubmed>
  7. <pubmed>23377345</pubmed>
  8. <pubmed>19972530</pubmed>
  9. Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.


1. Developmental Biology, 6th edition By Scott F Gilbert. Swarthmore College Sunderland (MA): Sinauer Associates; 2000. ISBN-10: 0-87893-243-7

Links: | 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: | Human Embryology and Morphology

Historical images of past understandings on respiratory development

3. YouTube Video explaining early respiratory development

4. Lavoisier

<pubmed>5323506</pubmed>

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 [1]. 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[2].

NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:[3]

  • Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development[1]
  • Maternal diabetes – high levels of insulin can delay surfactant synthesis[4]
  • Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity [4]
  • Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy [4]
  • Preterm Caesarean delivery – not allowing for lung maturation[5]
  • Genetic abnormalities that impair surfactant synthesis (ABCA3)[6]
  • Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid[7].

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. [7][8].

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. [9].

Problems associated with Meconium aspiration include[7]:

  • 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[10]. The complications can occur from a number of reasons following treatment[11]:

  • 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 [12].
  • 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)[13]. 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[14][15]. 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[16]. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) [17]. Genetic abnormalities have been identified as having an association with AL [18].

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[19]. Reviews have revealed that most cases are fatal[20] but ex-utero partum treatments (EXIT) have been successful in treating this condition[21]

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. [22]

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[23]. 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[24]. 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. [25].

  • 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): [26].

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

References

  1. 1.0 1.1 <pubmed>20468585</pubmed>
  2. <pubmed>6071188</pubmed>
  3. <pubmed>10829971</pubmed>
  4. 4.0 4.1 4.2 <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
  5. <pubmed>14629318</pubmed>
  6. <pubmed>15044640</pubmed>
  7. 7.0 7.1 7.2 <pubmed>10612363</pubmed>
  8. <pubmed>16651329</pubmed>
  9. <pubmed>19399004</pubmed>
  10. <pubmed>22785261</pubmed>
  11. <pubmed>19712501</pubmed>
  12. <pubmed>25031518</pubmed>
  13. <pubmed>24685676</pubmed>
  14. <pubmed>16928707</pubmed>
  15. <pubmed>22763554</pubmed>
  16. <pubmed>14325849</pubmed>
  17. <pubmed>2342705</pubmed>
  18. <pubmed>3566610</pubmed>
  19. <pubmed>22167132</pubmed>
  20. <pubmed>12778398</pubmed>
  21. <pubmed>9802816</pubmed>
  22. <pubmed>16798587</pubmed>
  23. <pubmed>24672262</pubmed>
  24. <pubmed>21355683</pubmed>
  25. <pubmed>21762550</pubmed>
  26. <pubmed>16333920</pubmed>


<pubmed>22151899</pubmed> <pubmed>22214468</pubmed> <pubmed>12547712</pubmed>

Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia 01.jpg

A: Thoracic X-Ray of newborn showing CDH. Loops of bowel can be seen compressing on the developing left lung in the pleural cavity. B: Loops of bowel seen enters through the diaphragmatic Hernia. C: Surgical procedure to the contents of the hernia back into the correct anatomical position. D: Extreme hypoplasia of left lung and slight hypoplasia of right lung revealed in autopsy of newborn suffering from CDH.

Thoracoscopic surgical repair of Human CDH

Laryngo-tracheo-oesophageal clefts