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Author(s):  Matthew Velkey, 2009 License:  Unless otherwise noted, this material is made available under the terms of the ...
Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicy  Use + Share + Adapt Make Your Own Assess...
Development of the  Respiratory System and Diaphragm Matt Velkey Spring 2009
The respiratory tract is derived from foregut endoderm and associated mesoderm <ul><li>Lateral folding: </li></ul><ul><li>...
The respiratory tract is derived from foregut endoderm and associated mesoderm <ul><li>From endoderm: </li></ul><ul><li>ep...
The lung buds form during the 4 th  week <ul><li>Initially appear as the  respiratory diverticulum , which is a ventral ou...
Splitting of foregut into esophagus and trachea <ul><li>Tracheo-esophageal ridges: longitudinal ridges that eventually fus...
Tracheo-esophageal fistulas <ul><li>Incomplete separation and/or atresia of trachea and esophagus  (B on right shows esoph...
Tracheoesophageal Fistulas / Esophageal Atresia <ul><li>Occur in approx 1/3000 births, most (90%) are that shown in (A) ab...
Tracheoesophageal fistula  in a male fetus with Trisomy 18 at 17 weeks. The upper esophageal segment ends blindly (pointer...
Tracheal atresia: Lungs bud off esophagus Clinical Correlation: Carlson.  Human Embryology and Developmental Biology.
Successive stages in the development of the larynx: The epithelial lining of the larynx is of endodermal origin.  The cart...
Clinical Correlation: Laryngeal Atresia This rare anomoly results in obstruction of the upper airway - congenital high air...
4 weeks 10 weeks 11 weeks 14 weeks - photomicrograph Progressive changes in the development of the laryngotracheal tube: E...
Growth of lungs into the body cavity <ul><li>Foregut endoderm surrounded by visceral (splanchnopleuric) mesoderm and  susp...
Differentiation of pleural membranes The lung buds “punch” into the visceral mesoderm. The mesoderm, which covers the outs...
Pleuropericardial folds separate pleural and pericardial cavities. 5 weeks - pleuropericardial fold forms 8 weeks - lungs ...
<ul><li>As the embryo folds, a connective tissue structure, the  septum transversum  forms between the heart and body stal...
Separating the abdominal and thoracic cavities:  development of the septum transversum and diaphragm <ul><li>Extension of ...
Separating the abdominal and thoracic cavities:  development of the septum transversum and diaphragm <ul><li>The septum tr...
Congenital Diaphragmatic Hernias <ul><li>Relatively common (1/2000 births) </li></ul><ul><li>Hiatal hernias are most frequ...
First three branching events are stereotyped: After the initial bifurcation into two primary bronchi, two buds, or seconda...
Dissected embryonic mouse lung: Right side cultured unperturbed after dissection (i.e. covered by lung mesenchyme). Left b...
Signaling molecules known to be important for lung budding and branching morphogenesis
Development of the human lung 7 trachea; 1 Left main bronchus; 6 right main bronchus; others lobes Source Undetermined
By the end of the sixth month, 17 generations of subdivisions have formed.  Six more divisions occur during postnatal life...
Stages of Maturation of the Lungs Pseudoglandular Period  (5-17 weeks): By 17 weeks, all major elements have formed, excep...
Canalicular Period:  (16th-26th week) Terminal Sac Period: (24th weeks to birth) Type I squamous cells Alveolar Period: (l...
At birth: Alveoli continue to mature after birth, become more muscular.  Growth of lungs after birth due primarily to incr...
Surfactant proteins augment function of phospholipid surfactants <ul><li>Four major surfactant proteins: A, B, C, and D </...
Clinical Correlations: Respiratory Distress Syndrome/Hyaline Membrane Disease: This disease affects 2% of live newborn inf...
Clinical Correlations: Congenital Lung Cysts:  Cysts (filled with fluid or air) are thought to be formed by the dilation o...
<ul><li>Slide 4: Langman’s Medical Embryology, 9th ed. 2004. (Both Images) </li></ul><ul><li>Slide5: Human Embryology and ...
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05.26.09(b): Development of the Respiratory System and Diaphragm

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  • Fig 13.1A from Sadler (2006). Langman’s Medical Embryology, 10 th ed.
  • Left figure: Fig 11-4 from Schoenwolf et al. (2009). Larsen’s Human Embryology, 4 th ed. Right figure: Fig 13.3 from from Sadler (2006). Langman’s Medical Embryology, 10 th ed.
  • Left: Fig 13.6A Right: Fig 13.7
  • Schoenwolf et al: Larsen’s Human Embryology, 4 th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. All rights reserved
  • Carlson: Human Embryology and Developemental Biology, 4 th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc. All rights reserved.
  • Fig 15-25 from Carlson (2009). Human Embryology and Developmental Biology, 4 th ed.
  • Transcript of "05.26.09(b): Development of the Respiratory System and Diaphragm"

    1. 1. Author(s): Matthew Velkey, 2009 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution – Non-Commercial – Share Alike 3.0 License : http://creativecommons.org/licenses/by-nc-sa/3.0/ We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact [email_address] with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use. Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised : Some medical content is graphic and may not be suitable for all viewers.
    2. 2. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicy Use + Share + Adapt Make Your Own Assessment Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation License Creative Commons – Zero Waiver Public Domain – Ineligible : Works that are ineligible for copyright protection in the U.S. (USC 17 § 102(b)) *laws in your jurisdiction may differ Public Domain – Expired : Works that are no longer protected due to an expired copyright term. Public Domain – Government : Works that are produced by the U.S. Government. (USC 17 § 105) Public Domain – Self Dedicated : Works that a copyright holder has dedicated to the public domain. Fair Use : Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (USC 17 § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis  to determine whether or not your use will be Fair. { Content the copyright holder, author, or law permits you to use, share and adapt. } { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } { Content Open.Michigan has used under a Fair Use determination. }
    3. 3. Development of the Respiratory System and Diaphragm Matt Velkey Spring 2009
    4. 4. The respiratory tract is derived from foregut endoderm and associated mesoderm <ul><li>Lateral folding: </li></ul><ul><li>Parietal (aka somatic) mesoderm lines embryonic body cavity (coelom) </li></ul><ul><li>Visceral (aka splanchnic) mesoderm covers endodermal gut tube </li></ul><ul><li>Gut tube suspended from body wall by dorsal mesentery </li></ul><ul><li>Cranio-caudal folding: </li></ul>Langman’s Medical Embryology, 9 th ed. 2004. (Both Images)
    5. 5. The respiratory tract is derived from foregut endoderm and associated mesoderm <ul><li>From endoderm: </li></ul><ul><li>epithelial lining of trachea, larynx, bronchi, alveoli </li></ul><ul><li>From splanchnic mesoderm: cartilage, muscle, and connective tissue of tract and visceral pleura. </li></ul>Human Embryology and Developmental Biology, 4 th ed. 2009.
    6. 6. The lung buds form during the 4 th week <ul><li>Initially appear as the respiratory diverticulum , which is a ventral outgrowth of foregut endoderm </li></ul><ul><li>MESODERM dependent process : Retinoic acid produced by adjacent mesoderm induces expression of TBX4 in foregut endoderm. TBX4 induces growth and differentiation of the trachea and lungs. </li></ul>Langman’s Medical Embryology, 10 th ed
    7. 7. Splitting of foregut into esophagus and trachea <ul><li>Tracheo-esophageal ridges: longitudinal ridges that eventually fuse to separate trachea from esophagus. </li></ul>Langman’s Medical Embryology, 9 th ed. 2004.
    8. 8. Tracheo-esophageal fistulas <ul><li>Incomplete separation and/or atresia of trachea and esophagus (B on right shows esophageal atresia) </li></ul><ul><li>Defect likely in mesoderm and usually associated with other defects involving mesoderm (cardiovascular malformations, VATER / VACTERL, etc.) </li></ul><ul><li>VATER = V ertebral anomalies, A nal atresia, T racheoesophageal fistula, E sophageal atresia, R enal atresia </li></ul><ul><li>VACTERL = VATER + C ardiac defects & L imb defects </li></ul>Langman’s Medical Embryology, 10 th ed. 2006. Larsen’s Human Embryology, 4 th edition. 2008.
    9. 9. Tracheoesophageal Fistulas / Esophageal Atresia <ul><li>Occur in approx 1/3000 births, most (90%) are that shown in (A) above. </li></ul><ul><li>Complications: </li></ul><ul><ul><li>PRENATAL: Polyhydramnios (due to inability to swallow amniotic fluid in utero) </li></ul></ul><ul><ul><li>POSTNATAL </li></ul></ul><ul><ul><ul><li>Gastrointestinal: Infants cough and choke when swallowing because of accumulation of excessive saliva in mouth and upper respiratory tract. Milk is regurgitated immediately after feeding. </li></ul></ul></ul><ul><ul><ul><li>Respiratory: Gastric contents may also reflux into the trachea and lungs, causing choking and often leading to pneumonitis. </li></ul></ul></ul><ul><li>Surgical repair (neonatal or in utero ) now result in 85% survival rates. </li></ul>Langman’s Medical Embryology, 10 th ed. 2006.
    10. 10. Tracheoesophageal fistula in a male fetus with Trisomy 18 at 17 weeks. The upper esophageal segment ends blindly (pointer). Clinical Correlation: Carlson. Human Embryology and Developmental Biology.
    11. 11. Tracheal atresia: Lungs bud off esophagus Clinical Correlation: Carlson. Human Embryology and Developmental Biology.
    12. 12. Successive stages in the development of the larynx: The epithelial lining of the larynx is of endodermal origin. The cartilages and muscles of the larynx arise from mesenchyme from the 4th and 6th pharyngeal arches 4 weeks 10 weeks 5 weeks 6 weeks Source Undetermined
    13. 13. Clinical Correlation: Laryngeal Atresia This rare anomoly results in obstruction of the upper airway - congenital high airway obstruction syndrome (CHAOS). The atresia or stenosis causes lower airways to become dilated, lungs to enlarge and become echogenic and the diaphragm becomes flattened or inverted. Can be detected by ultrasound. Laryngeal Web This uncommon anomaly results from incomplete recanalization of the larynx during the 10th week. A membranous web forms at the level of the vocal cords, partially obstructing the airway
    14. 14. 4 weeks 10 weeks 11 weeks 14 weeks - photomicrograph Progressive changes in the development of the laryngotracheal tube: Endodermal lining distal to the larynx differentiates into the epithelium and glands of the trachea and pulmonary epithelium. The cartilage, connective tissue and muscles of the trachea derive from splanchnic mesenchyme. Source Undetermined (All Images)
    15. 15. Growth of lungs into the body cavity <ul><li>Foregut endoderm surrounded by visceral (splanchnopleuric) mesoderm and suspended in body wall by dorsal mesentery </li></ul><ul><li>As lungs grow, they expand into the body cavity </li></ul>Larsen. Essentials of Human Embryology. 1998. Larsen. Essentials of Human Embryology. 1998.
    16. 16. Differentiation of pleural membranes The lung buds “punch” into the visceral mesoderm. The mesoderm, which covers the outside of the lung, develops into the visceral pleura . The somatic mesoderm, covering the body wall from the inside, becomes the parietal pleura . The space between is the pleural cavity . Langman’s Medical Embryology, 9 th ed. 2004.
    17. 17. Pleuropericardial folds separate pleural and pericardial cavities. 5 weeks - pleuropericardial fold forms 8 weeks - lungs grow and expand into pleural cavity 6 weeks - pleuropericardial membrane reaches midline 7 weeks -further maturation of pericardium (expands pleural cavity Moore and Persaud. The Developing Human.
    18. 18. <ul><li>As the embryo folds, a connective tissue structure, the septum transversum forms between the heart and body stalk. </li></ul>Separating the abdominal and thoracic cavities: development of the septum transversum and diaphragm Source Undetermined
    19. 19. Separating the abdominal and thoracic cavities: development of the septum transversum and diaphragm <ul><li>Extension of the septum transversum partially divides abdominal and thoracic cavities </li></ul><ul><li>Grows in a roughly transverse plane from front to back </li></ul><ul><li>Angled downward such that front of septum is at about T7, back edge is at about T12 </li></ul>Carlson. Human Embryology and Developmental Biology, 4 th ed. 2009.
    20. 20. Separating the abdominal and thoracic cavities: development of the septum transversum and diaphragm <ul><li>The septum transversum stops at the gut tube, leaving two open passageways on the left and right sides, aka the “pericardioperitoneal canals” (shown on the left) </li></ul><ul><li>Closing off these canals requires growth from the dorsolateral body wall, aka the “pleuroperitoneal membranes” (shown on the right) </li></ul><ul><li>Defects in this process cause CDH (congenital diaphragmatic hernias): abdominal contents herniate into pleural cavities and interfere with lung development. </li></ul>
    21. 21. Congenital Diaphragmatic Hernias <ul><li>Relatively common (1/2000 births) </li></ul><ul><li>Hiatal hernias are most frequent, but effects are rather minor due to small size of defect </li></ul><ul><li>Hernias due to failure of one or both pleurpericardial membranes to close off pericardioperitoneal canals have much more significant clinical impact because herniated abdominal contents interfere with lung development. </li></ul><ul><li>80-90% of hernias with clinical impact are on the left side. Large defects have high mortality due to extent of lung hypoplasia and dysfunction </li></ul>Langman’s Medical Embryology, 9th ed. 2004. Figure 11.9
    22. 22. First three branching events are stereotyped: After the initial bifurcation into two primary bronchi, two buds, or secondary bronchi, form on the left and three on the right predicting the five lobes of the adult human lung. Ten tertiary (segmental) bronchi form in the right lung and eight in the left lung - establishing the brochopulmonary segments of the adult human lung. (10) Segmental bronchi (7-8) Initial Patterning of the Lung:
    23. 23. Dissected embryonic mouse lung: Right side cultured unperturbed after dissection (i.e. covered by lung mesenchyme). Left bronchial tip covered with tracheal mesenchyme. Note no branching occurs at left bronchial tip due to tracheal mesenchyme inhibition. Endodermal/Mesenchymal Interactions Important for Branching Morphogenesis Source Undetermined
    24. 24. Signaling molecules known to be important for lung budding and branching morphogenesis
    25. 25. Development of the human lung 7 trachea; 1 Left main bronchus; 6 right main bronchus; others lobes Source Undetermined
    26. 26. By the end of the sixth month, 17 generations of subdivisions have formed. Six more divisions occur during postnatal life for a total of 23 branching events in the adult human lung. Branching continues to be regulated by epethelial-mesenchymal interactions (deriving from endodermal epithelial lung buds and the splanchnic mesoderm surrounding them). During branching, the bronchial tree is assuming an increasingly caudal (posterior) position. At birth, the tracheal bifurcation is adjacent to the fourth thoracic vertebra (T4).
    27. 27. Stages of Maturation of the Lungs Pseudoglandular Period (5-17 weeks): By 17 weeks, all major elements have formed, except those involved with gas exchange (fetuses unable to survive if born at this stage). Canalicular Period (16-25 weeks): Bronchi, terminal bronchioles become larger, lung tissue becomes highly vascular. Alveolar ducts form by week 24. By end, some terminal sacs have formed so respiration is possible (small chance of survival at this stage). Terminal Sac Period (24 weeks to birth): Many more terminal sacs develop, their epithelium becomes very thin and capillaries bulge into the developing alveoli. Blood-air barrier becomes well-developed. (By 26-28 wks, 1000 gr fetus has a sufficient # of sacs and surfactant to survive.) Alveolar Period (late fetal period to age 8): Alveoli-like structures are present by 32 weeks. Epithelial lining of sacs attenuate to extremely thin squamous epithelia, capable of gas exchange. 95% of characteristic, mature alveoli develop after birth. Moore and Persaud. The Developing Human.
    28. 28. Canalicular Period: (16th-26th week) Terminal Sac Period: (24th weeks to birth) Type I squamous cells Alveolar Period: (late fetal thru childhood, Type II, surfactant-producing cells) Development of lung tissue involved in air exchange Langman’s Medical Embryology, 9 th ed. 2004.
    29. 29. At birth: Alveoli continue to mature after birth, become more muscular. Growth of lungs after birth due primarily to increase of respiratory bronchioles and alveoli. Only 1/6 of adult alveoli present at birth. Lungs are fluid filled; fluid squeezed out and into lymphatics and blood vessels, expelled via trachea at delivery. Surfactant remains on surface, lowers air/blood tension.
    30. 30. Surfactant proteins augment function of phospholipid surfactants <ul><li>Four major surfactant proteins: A, B, C, and D </li></ul><ul><li>Surfactant A: activates macrophages to elicit uterine contractions, also important in host defense </li></ul><ul><li>Surfactant B: organizes into tubular structures that are much more efficient at reducing surface tension (specific deficiency in Surfactant B can lead to respiratory distress ) </li></ul><ul><li>Surfactant C: enhances function of surfactant phospholipids </li></ul><ul><li>Surfactant D: important in host defense. </li></ul>Gilbert, Scott. Developmental Biology . 2006.
    31. 31. Clinical Correlations: Respiratory Distress Syndrome/Hyaline Membrane Disease: This disease affects 2% of live newborn infants, with prematurely born being most susceptible. 30% of all neonatal disease results from HMD or its complications. Surfactant deficiency is the major cause of RDS or HMD. The lungs are underinflated and the alveoli contain a fluid of high protein content, probably derived from circulation substances and injured pulmonary epithelium. In addition to prematurity, prolonged intrauterine asphyxia may produce irreversible changes in Type II alveolar cells, rendering them incapable of producing surfactant. Other factors may contribute to surfactant deficiency, but the genetics of surfactant production are not well-defined. Prolonged, labored breathing damages alveolar epithelium, leading to protein deposition, or “hyaline” changes (shown in figure).
    32. 32. Clinical Correlations: Congenital Lung Cysts: Cysts (filled with fluid or air) are thought to be formed by the dilation of terminal bronchi, probably due to irregularities in later development. If severe, cysts are visible on radiographs. Highly variable outcomes result from different cystic conditions. Agenesis of the Lungs: Can occur bilaterally or unilaterally. Unilateral lung agenesis is compatible with live as remaining side hyperexpands and compensates. Lung Hypoplasia : Often caused by congenital diaphragmatic hernias or congenital heart disease. Characterized by reduced lung volume. Extreme hypoplasia is inconsistent with life.
    33. 33. <ul><li>Slide 4: Langman’s Medical Embryology, 9th ed. 2004. (Both Images) </li></ul><ul><li>Slide5: Human Embryology and Developmental Biology, 4th ed. 2009. </li></ul><ul><li>Slide 6: Langman’s Medical Embryology, 10th ed </li></ul><ul><li>Slide 7: Langman’s Medical Embryology, 9th ed. 2004. </li></ul><ul><li>Slide 8: Fig 11-4 from Schoenwolf et al. (2009). Larsen’s Human Embryology, 4 th ed; Fig 13.3 from from Sadler (2006). Langman’s Medical Embryology, 10 th ed. </li></ul><ul><li>Slide 9: Langman’s Medical Embryology, 10th ed. 2006. </li></ul><ul><li>Slide 10: Carlson. Human Embryology and Developmental Biology. </li></ul><ul><li>Slide 11: Carlson. Human Embryology and Developmental Biology. </li></ul><ul><li>Slide 12: Source Undetermined </li></ul><ul><li>Slide 14: Source Undetermined (All Images) </li></ul><ul><li>Slide 15: Larsen. Essentials of Human Embryology. 1998. </li></ul><ul><li>Slide 16: Langman’s Medical Embryology, 9th ed. 2004 </li></ul><ul><li>Slide 17: Moore and Persaud. The Developing Human. </li></ul><ul><li>Slide 18: Source Undetermined </li></ul><ul><li>Slide 19: Human Embryology and Developmental Biology, 4th ed. 2009. </li></ul><ul><li>Slide 20: Schoenwolf et al: Larsen’s Human Embryology, 4 th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc.; Schoenwolf et al: Larsen’s Human Embryology, 4 th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. </li></ul><ul><li>Slide 21: Moore and Persaud. The Developing Human. </li></ul><ul><li>Slide 22: Carlson: Human Embryology and Developemental Biology, 4 th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc. </li></ul><ul><li>Slide 23: Source Undetermined </li></ul><ul><li>Slide 24: Carlson: Human Embryology and Developemental Biology, 4 th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc. </li></ul><ul><li>Slide 25: Source Undetermined </li></ul><ul><li>Slide 27: Moore and Persaud. The Developing Human. </li></ul><ul><li>Slide 28: Langman’s Medical Embryology, 9th ed. 2004. </li></ul><ul><li>Slide 30: Gilbert, Scott. Developmental Biology . 2006. </li></ul><ul><li>Slide 31: Carlson: Human Embryology and Developemental Biology, 4 th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc. </li></ul>Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy
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