Slideshow is from the University of Michigan Medical School's M1 Embryology sequence View additional course materials on Open.Michigan: openmi.ch/med-M1Embryology

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.

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3. Development of the Respiratory System and Diaphragm Matt Velkey Spring 2009

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. Tracheal atresia: Lungs bud off esophagus Clinical Correlation: Carlson. Human Embryology and Developmental Biology.

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. 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. 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)

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. 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.

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. 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. Signaling molecules known to be important for lung budding and branching morphogenesis

25. Development of the human lung 7 trachea; 1 Left main bronchus; 6 right main bronchus; others lobes Source Undetermined

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. 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. 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. 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.

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. 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.