Embryonic Development of the Respiratory System PDF

(003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY...

(003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY OUTLINE - intermediate mesoderm I. THE GUT TUBE and the BODY CAVITY o Contributes to the urogenital system A. Formulation of Body Cavity - lateral plate mesoderm B. Serous Membranes o Involved in forming the body cavity C. Abdominal Cavity The lateral plate mesoderm split into two layers: D. Diaphragm and Thoracic Cavity - Parietal (somatic) Layer E. Formation of Diaphragm o Adjacent to the surface ectoderm (or the II. RESPIRATORY SYSTEM outer part) and continuous with the A. The Lung Bud form During the 4th Week extraembryonic parietal mesoderm layer B. Splitting of the Foregut into Esophagus over the amnion. and Trachea - Visceral (splanchnic) Layer C. Trachea – Esophagial Fistulas Adjacent to the endoderm forming the gut tube and continuous D. Clinical Correlations with the visceral layer of the extraembryonic mesoderm covering 1. Tracheoesophagial Fistula the yolk sac. 2. Tracheal Agenesis III. GROWTH of LUNGS into the BODY CAVITY A. Differentiation of Pleural Membranes B. Pleuropericardial Folds Separate Pleural and Pericardial Cavities C. Extension of the Septum Trannsversum Partially Divides Abdominal and Thoracic Cavities D. Congenital Diaphragmatic Hernia E. Initial Patterning of the Lung IV. DEVELOPMENT of HUMAN LUNG A. Endodermal/Mesenchymal Interactions B. Signaling Molecules C. Stages of Maturation of the Lungs 1. Pseudoglandular Period(5-17 Weeks) Figure 1. Mesodermal Layers 2. Canalicular Period (16-26 Together, the visceral (splanchnic) layer of lateral plate Weeks) mesoderm and underlying endoderm are called the 3. Terminal Sac Period (26 Weeks splanchnopleure. to Birth) 4. Alveolar Period (Late Fetal The space created between the two layers of lateral plate Period to Age 8) mesoderm constitutes the primitive body cavity. D. Development of Lung Tissue (Air On the central axis, we have the neural tube and the Exchange) derivatives of the mesoderm (Paraxial, Intermediate and E. Surfactant Proteins Augment Function of Lateral Plate Mesoderm). Phospholipid Surfactants The Lateral Plate Mesoderm will split into two forming the F. Clinical Correlations primitive body cavity formation. 1. Respiratory Distress Sndrome The one that will be continuous with the ectoderm is the 2. Hyaline Membrane Disease somatic while the splanchnic will be near the endoderm. 3. Congenital Lung Cysts During the 4th week, the sides of the embryo begin to 4. Agenesis of Lungs grow ventrally forming two lateral body wall folds. 5. Lung Hypoplasia - Lateral body wall folds 6. Diaphragmatic Hernias o consist of the parietal layer of the lateral plate mesoderm, overlying ectoderm, and the cell from the adjacent somites that I. THE GUT TUBE AND THE BODY CAVITIES migrate into the mesoderm layer across the lateral somitic frontier. FORMATION OF THE BODY CAVITY As these folds progress, the endoderm layer also folds At the end of the3rd week, intra embryonic mesoderm ventrally and closes to form the gut tube. differentiates into paraxial mesoderm, which forms By the end of the 4th week, the lateral body wall folds somitomeres and somites that play a major role in meet in the midline and fuse to close the ventral body forming the skull and vertebrae walls. Page 1 of 12 CMED 1D  (003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY This closure is aided by growth of the head and tail membranes lining the outside of the peritoneal, pleural, regions (folds) that cause the embryo to curve into the and pericardial cavities. fetal position. The parietal layer is in the outermost part of the serous Closure of the ventral body wall is complete except in the membranes. region of the connecting stalk (future umbilical cord). In a similar manner, cells of the visceral layers of the Similarly, closure of the gut tube is complete except for a lateral plate mesoderm form the visceral layer of the connection from the midgut region to the yolk sac that serous membranes covering the abdominal organs, forms the vitelline duct (yolk sac). lungs and heart. - This duct is incorporated into the umbilical cord, Abdominal (Peritoneal Serous Membrane), Lungs becomes very narrow, and degenerates between the (Pleural Serous Membrane) and the Heart (Pericardial second and third months of gestation. Serous Membrane) (Note that throughout the process of body cavity and gut Serous membranes are made up of simple cuboidal tube development, the parietal and visceral layers of epithelium. lateral píate mesoderm are continuous with each other at the junction of the gut tube with the posterior body wall). ABDOMINAL CAVITY Visceral and parietal layers of serous membrane are continuous with each other as the dorsal mesentery (like an anchor), which suspends the gut tube from the posterior body wall into the peritoneal cavity. Dorsal mesentery extends continuously from the caudal limit of the foregut to the end of the hindgut Ventral mesentery exists only from the caudal foregut to the upper portion of the duodenum and results from thinning of mesoderm of the septum transversum. These mesenteries are double layers (Outer parietal and inner visceral layer) of the peritoneum that provide a pathway for blood vessels, nerves, and lymphatics to the organs. DIAPHRAGM and THORACIC CAVITY The septum transversum is a thick plate of mesodermal tissue occupying the space between the thoracic cavity Figure 2. Lateral Folding and the stalk of the yolk sac. - The septum is derived from visceral (splanchnic) mesoderm surrounding the heart and assumes its position between the primitive thoracic and abdominal cavities when the cranial end of the embryo grows and curves into the fetal position. This septum does not separate the thoracic and abdominal cavities completely but leaves large openings, the pericardioperitoneal canals, on each side of the foregut. Parietal (somatic) mesoderm lines embryonic body cavity (coelom) Visceral (Splanchnic) mesoderm covers endodermal gut tube Gut tube suspended from body wall by dorsal mesentery. When lung buds begin to grow, they expand caudolaterally within the pericardioperitoneal canals. As a result of the rapid growth of the lungs, the Figure 3. Cranio-Caudal Folding pericardioperitoneal canals become too small, and the lungs begin to expand into the mesenchyme of the body SEROUS MEMBRANES wall dorsally, laterally, and ventrally. Some cells of the parietal layer of the lateral plate Ventral and lateral expansion is posterior to the mesoderm lining the intraembryonic cavity become pleuropericardial folds. mesothelial and form the parietal layer of the serous Page 2 of 12 CMED 1D  (003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY At first, these folds appear as small ridges projecting into This explains why further expansion of the lungs and the primitive undivided thoracic cavity. descent of the septum shift the phrenic nerves that With expansión of the lungs, mesoderm of the body wall innervate the diaphragm into the fibrous pericardium. forms two components the definitive wall of the thorax Although the septum transversum lies opposite cervical and the pleuropericardial membranes, which are segments during the fourth week, by the sixth week, the extensions of the pleuropericardial folds that contain the developing diaphragm is at the level of thoracic somites. common cardinal veins and phrenic nerves. The repositioning of the diaphragm is caused by rapid Subsequently, descent of the heart and positional growth of the dorsal part of the embryo (vertebral changes of the sinus venosas shift the common cardinal column), compared with that of the ventral part. veins toward the midline, and the pleuropericardial By the beginning of the third month, some of the dorsal membranes are drawn out in mesentery-like fashion. bands of the diaphragm originate at the level of the first Finally, they fuse with each other and with the root of the lumbar vertebra. lungs, and the thoracic cavity is divided into the definitive The phrenic nerves supply the diaphragm with its motor pericardial cavity and two pleural cavities. and sensory innervation. In the adult, the pleuropericardial membranes form the Because the most peripheral part of the diaphragm is fibrous pericardium. derived from mesenchyme of the thoracic wall, it is generally accepted that some of the lower intercostal FORMATION OF DIAPHRAGM (thoracic) nerves contribute sensory fibers to the Although the pleural cavities are separate from the peripheral part of the diaphragm. pericardial cavity, they remain in open communication with the abdominal (peritoneal) cavity by way of the pericardioperitoneal canals. During further development, the opening between the prospective pleural and peritoneal cavities is closed by crescent- shaped folds, the pleuroperitoneal folds, which project into the caudal end of the pericardioperitoneal canals. Gradually, the folds extend medially and ventrally, so that by the seventh week, they fuse with the mesentery of the esophagus and with the septum transversum. Hence, the connection between the pleural and peritoneal portions of the body cavity is closed by the pleuroperitoneal membranes. Further expansion of the pleural cavities relative to mesenchyme of the body wall adds a peripheral rim to the pleuroperitoneal membranes. Once this rim is established, myoblasts originating from somites at cervical segments three to five (C3-5) penetrate the membranes to form the muscular part of the diaphragm. Thus, the diaphragm is derived from the following structures: - The septum transversum, which forms the central Figure 4. Embryology of the Diaphragm. The respiratory tract is tendon of the diaphragm derived from the foregut endoderm and associated mesoderm. - The two pleuroperitoneal membranes - Muscular components from somites at cervical segments three to five II. RESPIRATORY SYSTEM - The mesentery of the esophagus, in which the crura 4th week of the diaphragm develop. Endodermal derivative (origin) - Epithelium of the internal lining of Larynx, During the fourth week, the septum transversum lies trachea, bronchi, Lungs opposite cervical somites, and nerve components of the Splanchnic Mesoderm third, fourth, and fifth cervical segments of the spinal - Cartilage, muscle and connective tissue cord grow into the septum. components of the trachea and lungs At first, the nerves, known as phrenic nerves, pass into Respiratory diverticulum (lung bud) formation from the the septum through the pleuropericardial folds. ventral wall of foregut. Page 3 of 12 CMED 1D  (003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY Mesoderm increases production of Retinoid Acid. (Vitamin A) - Upregulates TF TBX4 The appearance and location of the lung bud are dependent upon an increase in retinoic acid (RA) produced by adjacent mesoderm. This increase in RA causes upregulation of the transcription factor TBX4 expressed in the endoderm of the gut tube at the site of the respiratory diverticulum. TBX4 induces formation of the bud and the continued growth and differentiation of the lungs. Lung bud initially has open communication with the foregut. Figure 6. Sagittal section through the cephalic end of a 5-week Caudal expansion embryo showing the openings of the pharyngeal pouches and the When the diverticulum expands caudally, however, two laryngotracheal orifice. longitudinal ridges, the tracheoesophageal ridges, separate it from the foregut. THE LUNG BUD FORM DURING THE 4TH WEEK When tracheoesophageal ridges fuse to form Initially appear as the respiratory diverticulum, which is a tracheoesophageal septum, foregut is divided into: ventral outgrowth of foregut endoderm. - Dorsal portion – esophagus Mesoderm dependent process. - Ventral portion – Trachea and Lung buds Retinoic Acid produced by adjacent mesoderm induces Respiratory primordium maintains laryngeal expression of TBX4 in foregut endoderm. TBX4 induces communication with the pharynx through the laryngeal growth and differentiation of the trachea and lungs. orifice. The respiratory tract is derived from foregut endoderm and associated mesoderm. SPLITTING of the FOREGUT INTO ESOPHAGUS and TRACHEA Trachea-esophageal ridges: longitudinal ridges that eventually fuse to separate trachea from esophagus. Figure 7. Successive stages in development of the respiratory diverticulum showing the tracheoesophageal ridges and formation of the septum, splitting the foregut into esophagus and trachea with lung buds. Figure 5. Embryo to approximately 25 days, gestation showing the relation of the respiratory diverticulum to the heart, stomach, and liver. TRACHEO-ESOPHAGEAL FISTULAS Figure 8. Various types of esophageal atresia and/or TEFs. Page 4 of 12 CMED 1D  (003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY Incomplete separation and or atresia of trachea and Proximal portion of the esophagus has no connection esophagus (B on the right shows esophageal atresia) with the distal esophagus. The distal esophagus would Defect likely in mesoderm and usually associated with find its way connecting into trachea forming other defects involving mesoderm (cardiovascular tracheoesophageal fistula. malformations, VATER/VACTERL, etc.) VATER= Vertebral anomalies, Anal atresia, Tracheal Agenesis Tracheoesophageal fistula, Esophageal atresia, Renal - Lungs bud off esophagus atresia. VACTERL= VATER + Cardiac Defects and Limb Defects. (If the C and L are added, then there is an addition of the Cardiac Defects and Limb Defects) The most common for the tracheoesophageal type is the picture above (Labeled A). The upper part of the esophagus has no continuity with the lower esophagus that is why it is called proximal blind-end part of the esophagus and there will be a tracheoesophageal fistula of the lower distal part of the esophagus. Occurs in approx. 1/3000 births, most (90%) are that shown (A) above. Complications: - PRENATAL: Polyhydramnions (due to inability to swallow amniotic fluid in utero) - POSTNATAL: o Gastrointestinal: Infants cough and choke Figure 10. Tracheal Agenesis. when swallowing because of accumulation of excessive saliva in mouth and upper SUCCESSIVE STAGES in the DEVELOPMENT of respiratory tract. Milk is REGURGATED LARYNX IMMEDIATELY after feeding. The epithelial lining of the larynx is of endodermal origin, o Respiratory: Gastric contents may also which proliferates and temporarily OCCLUDES the reflux into the trachea and lungs, causing lumen of the larynx. A combination of apoptosis and choking and often leading to growth of the wall of the larynx allows recanalization by PNEUMONITIS. about 10 weeks. *SURGICAL REPAIR (NEONATAL OR UTERO) NOW RESULT The cartilages and muscles of the larynx arise from IN 85% SURVIVAL RATES.* mesenchyme from the 4th and 6th pharyngeal arches and are innervated by branches of the vagus nerves (4th arch CLINICAL CORRELATION by the superior laryngeal branch, 6th arch by the recurrent laryngeal branch.) Tracheoesophageal Fistula in male fetus with Trisomy 18 at 17 weeks. The upper esophageal segment ends blindly (pointer). Figure 11. Laryngeal orifice and surrounding swellings at Figure 9. Tracheoesophageal Fistula in male fetus. The upper successive stages of development. A. 6 weeks.B. 5 weeks c. 6 esophageal segment ends blindly (pointer). weeks D. 10 weeks. Page 5 of 12 CMED 1D  (003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY At 4TH week -Foramen cecum of the tongue, Hypopharyngeal eminence is also rare and the III. GROWTH of LUNGS INTO the BODY pharyngeal pouch gives rise to the three (3) and four (4) CAVITY area. And the presence of laryngeal groove. Foregut endoderm surrounded by visceral By 5th week- Hypopharyngeal eminence will extend (splanchnopleuric) mesoderm and suspend in body wall forming epiglottic swelling and presence of laryngeal by dorsal mesentery. inlet. By 6th week- The epiglottis will form and the laryngeal As lungs grow, they expand into the body cavity. inlet will enlarge. By the 10th week- already open. Vacuolization and recanalization produce a pair of lateral recesses, the laryngeal ventricles. These recesses are bounded by folds of tissue that differentiate into the false and true vocal cords all laryngeal muscles are innervated by branches of the 10th cranial nerve; the vagus nerve when mesenchyme of the two arches transforms into the thyroid, cricoid, and arytenoid cartilages, the characteristic adult shape of the laryngeal orifice can be recognized. CLINICAL CORRELATIONS Laryngeal Atresia - Failure of recanalization results in Figure 12. Formation of the dorsal mesentery. - obstruction of the upper airway – congenital high airway obstruction syndrome (CHAOS). The atresia or stenosis causes lower airways to DIFFERENTIATION of PLEURAL MEMBRANES The lung buds “punch” into the visceral mesoderm. The become dilated, lungs to enlarge and become mesoderm, which covers the outside of the lung, - echogenic and the diaphragm becomes develops into the visceral pleura. flattened or inverted. Can be detected by ultrasound. The somatic, covering the bodywall from the inside, becomes the parietal pleura. The space between is the Laryngeal Web pleural cavity. - Results from partial recanalization of the larynx o Pleural cavities are separate from the during the 10th week. A membranous web forms pericardial cavity, they remain in open at the level of communication with the abdominal (peritoneal) the vocal cords, partially obstructing the airway. cavity by way of the pericardioperitoneal canals - Progressive changes in the development of the o Further expansion of the pleural cavities laryngotracheal tube: relative to mesenchyme of the body wall adds - Endodermal lining distal to the larynx a peripheral rim to the pleuroperitoneal differentiates into the epithelium and glands of membranes the trachea and pulmonary epithelium. The cartilage, connective tissue and muscles of the trachea derive from splanchnic mesenchyme. - By 4th week – the lungs will be coming from the endoderm. In 10th week the epithelium is more prominent. By 11th week the smooth muscle will be evident and connects cartilage and by the 14th week its already recognizable (pseudostratified columnar ciliated epithelium w/ few goblet cells). Figure 13. Endoderm of the lower part of L-T Tube. Page 6 of 12 CMED 1D  (003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY Figure 14. A. Ventral view of the bronchial buds covered by visceral pleura. B. Once the pericardioperitoneal canals separate from the pericardial and peritoneal cavities, respectively, the lungs expand in the pleural cavities. Note the visceral and parietal pleural cavity. The visceral pleura extends between the lobes of the lungs. PLEUROPERICARDIAL FOLDS SEPARATE PLEURAL Figure 16. Development of the septum transversum. and PERICARDIAL CAVITIES Separating the abdominal and thoracic cavities: EXTENSION of the SEPTUM TRANSVERSUM development of the septum transversum and diaphragm. PARTIALLY DIVIDES ABDOMINAL and THORACIC As the embryo folds, a connective tissue structure, the CAVITIES septum transverum forms between the heart and body Grows in a roughly transverse plane from front to back stalk. Is initially at the level of C1 but is displaced caudally by Ventral and Lateral expansion is posterior to differential growth of the embryo. pleuropericardinal folds; these folds appear as small At week 5-6, myoblasts migrate into septum, carrying ridges projecting into the primitive undivided thoracic innervation with them (ventral rami from C3, 4, 5) cavity. - Hence, the course of the phrenic nerve As the lungs expand, mesoderm of the body wall splits By week 8, is angled downward such that front of septum into two components; (1) the definitive wall of the thorax is at about T7, back edge is at about T12 (similar to adult). and (2) the pleuropericardial membranes The septum transversum stops at the gut tube, leaving Pleuropericardial folds that contain the common cardinal two open passageways on the left and right sides, aka veins and phrenic nerves. Subsequently, descent of the the “pericardioperitoneal canals” (aka pleural canals, heart and positional changes of the sinus venosus shift shown on the left) the common cardinal veins toward Closing off these canals requires growth from the Finally, they fuse with each other and with the root of the dorsolateral body wall, aka the “pleuroperitoneal lungs, and the thoracic cavity is divided into the definitive membranes” (shown on right) pericardial cavity and two pleural cavities. Defects in this process cause CDH (congenital diaphragmatic hernias): abdominal contents herniate into pleural cavities and interfere with lung development. This septum does not separate the thoracic and abdominal cavities completely but leaves large opening the pericardioperitoneal canal. Figure 15. Development of the heart 5th to 8th week. Figure 17. Septum Transversum formation. Page 7 of 12 CMED 1D  (003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY All of these will be coming from the endoderm from the pharyngeal pouches 1,2,3. On the 28th day trachea only. On the 32nd day primary bronchial bud formation will be evident. And on the 33rd day (primary bronchi). On the 35th day there will be a lobe formation (right upper lobe, middle lobe and right lower lobe). And on the 7th week almost complete. Three secondary buds form on the right (corresponding to the 3 lobes on the right) ten tertiary(segmental) bronchi form in the right lung Eight bronchi form in the left lung establishing the 18 bronchopulmonary segments of the adult human lung. Figure 18. Extension of the septum transversum partially divides abdominal and thoracic cavities. CONGENITAL DIAPHRAGMATIC HERNIA relatively common (1/2000 births) Hiatal hernias are most frequent, but effects are rather minor due to small size of defect Hernias due to failure of one or both pleuroperitoneal membranes to close off pericardioperitoneal canals have much more significant clinical impact because herniated abdominal contents interfere with lung development. 80-90% of hernias with clinical impact are on the left side. Large defects have mortality due to extent of lung hypoplasia and dysfunction Figure 20. Development of the major branching patterns of the A large defect is associated with the high rate of mortality lungs. (75%) from pulmonary hypoplasia and dysfunction Types of diaphragmatic hernia; (1)parasternal hernia (2)esophageal hernia IV. DEVELOPMENT of HUMAN THING (Note : panel 1 is as viewed from the front ,panels 2& 3 are Parasternal hernia – defect is frequently seen in the as viewed from the back) anterior portion of the diaphragm 9=L inferior lobe primordium Esophageal hernia – congenital shortness of esophagus. Upper portions of the stomach are retained in the thorax and the stomach is constricted at the level of diaphragm. Figure 19. Congenital Diaphragmatic Hernia. INITIAL PATTERING of the LUNGS First three branching events are sterotyped : Trachea into two primary bronchi (left and right) Left primary bronchus into two secondary bronchus Figure 21. Human Lung Development. (corresponding to the two lobes of the left lung) Page 8 of 12 CMED 1D  (003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY ENDODERMAL / MESENCHYMAL INTERACTIONS cells secrete TGF10 secretion. Mesenchymal cells secrete TGFB which promotes deposition of ECM IMPORTANT for BRANCHING MORPHOGENESIS FGF10 signaling NOT inhibited at lateral aspects of both, Right side cultured unperturbed after dissection (ie. covered by lung mesenchyme) promoting growth on either side Left bronchial tip covered with tracheal mesenchyme. By the end of the 6th month, 17 generations of subdivisions Note no branching occurs at left bronchial tip due to tracheal have formed. Six more divisions occur during postnatal life for mesenchyme inhibition 23 branching events in the adult human lung Branching continues to be regulated by epithelial mesenchymal interactions (deriving from endodermal epithelial lung buds and splanchnic mesoderm surrounding them). Main Point: - Branching morphogenesis in the lungs in mesoderm and retinoid-dependent (among other factors).Late disruption may have minor effects whereas early disruption may result in hypoplasia or even agenesis. STAGES of MATURATION of the LUNGS A. Pseudoglandular Period (5-17 weeks) by 17 weeks, all major element have formed except those involved with gas exchange (fetuses unable to survive if born at this stage). Figure 22. Dissected embryonic mouse. Branching has continued to form terminal bronchioles SIGNALING MOLECULES KNOWN TO BE No respiratory bronchioles or alveoli are present B. Canalicular Period (16-26 weeks): IMPORTANT for LUNG BUDDING and Bronchi, terminal bronchioles become larger, lung BRANCHING MORPHOGENESIS tissue becomes high vascular. Surfactant production begins around 22, but not enough to prevent airway collapse (atelectasis). Alveolar ducts with terminal sacs form by week 24, so limited respiration is possible Respiration is possible at the end (26 weeks): some thin-walled terminal sacs (primordial alveoli) have developed; lung tissue is well vascularized Each terminal bronchiole divides into two or more respiratory bronchioles, which in turn divide into three to six alveolar ducts. C. Terminal Sac Period (26 weeks to birth): Many more terminal sacs develop, with very thin epithelium and capillaries bulging into the developing alveoli.Blood-air barrier becomes well developed. Surfactant production is sufficient to Figure 23. Signaling molecules known to be important for lung prevent atelectasis. budding and branching morphogenesis. A, The tip of an elongating Surfactant production begins at 20 to 22 weeks respiratory duct. Fibroblast growth factor-10 (FGF-10) secretion in the Terminal sacs (primitive alveoli) form, and capillaries mesenchyme stimulates the growth of the tip of the epithelial duct establish close contact toward it. B, The prelude to branching. Inhibition of FGF-10 signaling D. Alveolar Period (late fetal period to age 8): at the tip of the duct leads to stabilization of that area. C, Cleft Alveoli-like structures are present by 32 weeks. formation. Epithelial lining sacs attenuate lining o extremely thin Tbx/RA signaling induces mesenchyme to secret squamous epithelia, capable of gas exchange FGF10,which induces epithelial growth 95% of characteristic, mature alveoli develop after Branching initiated by BMP4 secretion of apical cells (arrests birth their proliferation). Epithelium also secrets Shh, which inhibits At 38 weeks, the lungs are capable of respiration mesenchyme proliferation and FGF0 secretion. Mesenchymal because the alveolocapillary membrane (pulmonary Page 9 of 12 CMED 1D  (003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY diffusion barrier or respiratory membrane) is SURFACTANT PROTEINS AUGMENT FUNCTION of sufficiently thin to allow gas exchange PHOSPHOLIPID SURFACTANTS At birth, mammalian lung is far from mature. Major mechanism for increase is the formation of secondary connective tissue septa that divide existing alveolar sacs Initially, the secondary septa are relatively thick. In time, they transform into thinner mature septa capable of full respiratory exchange function. Figure 26. The four major surfactant proteins; A, B, C, and D. Surfactant A: activates macrophage to elicit contractions, also important in host defense Surfactant B: organizes into tubular structure that are much more efficient at reducing surface tension (specific deficiency in Surfactant B can lead to respiratory distress) Surfactant C: enhances function of surfactant phospholipids Figure 24. Evaluation of fetal thorax under the microscope. A and Surfactant D: important in host defense. B, early stages of lung development. C and D alveolocapillary membrane is thin and that some capillaries bulge into the terminal sacs and alveoli. CLINICAL CORRELATIONS DEVELOPMENT of LUNG TISSUE INVOLVED IN AIR RESPIRATORY DISTRESS SYNDROME (HYALINE MEMBRANE DISEASE) EXCHANGE Affects 2% of live newborn, with prematurely born being most susceptible; 30% of all neonatal disease result 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, derived from circulation substances and injured pulmonary epithelium. In addition to prematurity, prolonged intrauterine asphyxia (impaired or absent exchange of oxygen and carbon dioxide) may produce irreversible changes in Type II alveolar cells, making them incapable of producing surfactant. Other factors (sepsis, aspiration, and pneumonia) may Figure 25. Histological development of the lung: Terminal Sac inactivate surfactant, leading to an absence of deficiency Period of Newborn. A. Canalicular Period (16-26th week) cuboidal of surfactant in premature and full-term infants cells lining the respiratory bronchiole, B. Terminal Sac Period (end Prolonged labored breathing damages alveolar of the 6th and beginning of the 7th prenatal month) Cuboidal cells epithelium leading to protein deposition, or “hyaline” become very thin and intimately associated with the endothelium changes. of blood and lymph capillaries or form terminal sacs [primitive alveoli), C. Alveolar Period (late fetal to childhood) thin squamous CONGENITAL LUNG CYSTS epithelial cells [alveolar epithelial cells, type I] and surrounding Cysts (filled with fluid or air) are thought to be formed by capillaries protruding into mature alveoli. the dilation of terminal bronchi Probably due to branching irregularities in late development. If several cysts are visible, the lungs have a honeycomb appearance on radiographs Lung cysts are usually located at the periphery of the lung Page 10 of 12 CMED 1D  (003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY AGENESIS OF LUNGS 2. Adjacent to the surface ectoderm (or the outer part) and Can occur bilaterally or unilaterally continuous with the extraembryonic parietal mesoderm layer Due to early failure of the respiratory bud to develop or over the amnion. branch (e.g. insufficient mesoderm) A. Intermediate Mesoderm Cause: teratogens (e.g. retinoic acid, alcohol or genetic B. Lateral Plate Mesoderm mutation) C. Parietal (Somatic) Layer Unilateral lung agenesis is compatible with life D. Visceral (Splanchnic) Layer o Existing side is hyperexpanded and compensates 3. Consist of the parietal layer of the lateral plate mesoderm, o Heart and other mediastinal structures are shifted overlying ectoderm, and the cell from the adjacent somites to the affected side that migrate into the mesoderm layer across the lateral somitic LUNG HYPOPLASIA frontier. Characterized by a markedly reduced lung volume and A. Lateral Body Wall Folds hypertrophy of smooth muscle in the pulmonary arteries B. Visceral (Splanchnic) Layer May be due to inadequate branching morphogenesis C. Parietal (Somatic) Layer Often caused by congenital diaphragmatic hernias or D. Vitelline Duct (Yolk Sac) congenital heart disease 4. It is a thick plate of mesodermal tissue occupying the space between the thoracic cavity and the stalk of the yolk sac. Extreme hypoplasia is inconsistent with life A. Pericardioperitoneal Canals DIAPHRAGMATIC HERNIAS B. Septum Transversum Lung is unable to develop normally because it is C. Dorsal Mesentery compressed by the abnormally positioned abdominal D. Ventral Mesentery viscera 5. It exists only from the caudal foregut to the upper portion of A congenital diaphragmatic hernia, one of the more the duodenum and results from thinning of mesoderm of the malformation in the newborn (1 per 2,000), is most septum transversum. frequently caused by failure of one or both of the A. Pericardioperitoneal Canals pleuroperitoneal membrane to close the B. Septum Transversum pericardioperitoneal canals. In that case, the peritoneal C. Dorsal Mesentery and pleural cavities are continuous with one another D. Ventral Mesentery along the posterior body wall. 6. It covers endodermal gut tube. Allows abdominal viscera to enter the plural cavity. In A. Intermediate Mesoderm 85% to 90% of cases, the hernia is on the left side, and B. Lateral Plate Mesoderm intestinal loops, stomach, spleen, and part of the liver C. Parietal (Somatic) Mesoderm may enter the thoracic cavity. The abdominal viscera in D. Visceral (Splanchnic) Mesoderm the chest push the heart anteriorly and compress the 7. Respiratory primordium maintains laryngeal communication lungs, which are commonly hypoplastic. with the pharynx through the _______. A large defect is associated with a high rate of mortality A. Respiratory Tract (75%) from pulmonary hypoplasia and dysfunction. B. Laryngeal Orifice Occasionally, a small part of the muscular fibers of the C. Foregut Endoderm diaphragm fails to develop, and a hernia may remain D. Tracheoesophageal Ridges undiscovered until the child is several years old. Such a 8. Longitudinal ridges that eventually fuse to separate trachea defect, frequently seen in the anterior portion of the from esophagus. diaphragm, is a parasternal hernia A small peritoneal sac A. Respiratory Diverticulum containing intestinal loops may enter the chest between B. Laryngeal Orifice the sternal and costal portions of the diaphragm. C. Foregut Endoderm Another type of diaphragmatic hernia, esophageal D. Tracheoesophageal Ridges hernia, is thought to be due to congenital shortness of the 9. It is the ventral outgrowth of foregut endoderm esophagus. Upper portions of the stomach are retained A. Respiratory Diverticulum in the thorax, and the stomach is constricted at the level B. Laryngeal Orifice of the diaphragm. C. Foregut Endoderm D. Tracheoesophageal Ridges TEST YOUR KNOWLEDGE 10. It is derived from foregut endoderm and associated 1. It contributes to the urogenital system. mesoderm. A. Intermediate Mesoderm A. Respiratory Tract B. Lateral Plate Mesoderm B. Laryngeal Orifice C. Parietal (Somatic) Layer C. Foregut Endoderm D. Visceral (Splanchnic) Layer D. Tracheoesophageal Ridges Page 11 of 12 CMED 1D  (003) EMBRYONIC DEVELOPMENT OF THE RESPIRATORY SYSTEM DR. NAME | MM/DD/YY 11. Initially appear as the respiratory diverticulum, which is a 19. It is thick plate of mesodermal tissue occupying the space ventral outgrowth of foregut endoderm. between the thoracic cavity and the stalk of the yolk sac. A. Serous membrane A. Lung bud B. Lung bud B. Foregut endoderm C. Lung cavity C. Septum tranversum D. thoracic cavity D. Pleuropericardial folds 12. This caused by the failure of one or both pleuroperitoneal 20. It contains the common cardinal veins and phrenic nerves. membranes to close off pericardioperitoneal canals have much Subsequently, descent of the heart and positional changes of more significant clinical impact because herniated abdominal the sinus venosus shift the common cardinal veins toward contents interfere with lung development. A. Lung bud A. Laryngeal web B. Foregut endoderm B. Laryngeal Atresia C. Septum tranversum C. Diaphragmatic hernia D. Pleuropericardial folds D. NOTA 13. It characterized by the progressive changes in the ACABDDBDAABCAABAACD development of the laryngotracheal tube A. Laryngeal web REFERENCES B. Laryngeal Atresia 1. PPT - Doc Gail Tanawit C. Diaphragmatic hernia 2. Langman's Medical Embryology by T.W. Sadler. 13th D. NOTA EDITION, Chapter 7: The Gut Tube and The Body 14. What nerve innervates the muscles in the larynx? Cavities. Pages 95-104; Chapter 14: Respiratory A. X System. Pages 218-224. B. IX C. XII D. XIII 15. It is caused by failure in recanalization as there is an obstruction in the upper airways thus making the lower airways to become dilated, lungs to enlarge and become echogenic and the diaphragm becomes flattened or inverted. A. Laryngeal web B. Laryngeal Atresia C. Diaphragmatic hernia D. NOTA 16. From which germ cells does the epithelial lining of the larynx originates? A.Endoderm B. Mesoderm C. Ectoderm D. NOTA 17. What type of surfactant activates macrophage to elicit contraction, also important in host defense? A. Surfactant A B. Surfactant B C. Surfactant C D. Surfactant D 18. What type of surfactant enhances function of surfactant phospholipids? A. Surfactant A B. Surfactant B C. Surfactant C D. Surfactant D Page 12 of 12 CMED 1D