You’re Only An Embryo Once

1. You’re Only An Embryo Once Review of Development of the Respiratory System

2. Embryonic Stage22 days to 6 weeks • Day 22: Formation of a ventral outpouching from the endodermal foregut—respiratory diverticulum • Grows ventrocaudally through mesenchyme around the foregut • Days 26-28: First bifurcation—primary bronchial buds which give rise to the right and left lungs • Proximal end of diverticulum forms the trachea and larynx • Glottis forms at the original point of the diverticulum

3. Embryonic Stage22 days to 6 weeks • 5th week: First round of branching • Highly stereotypical: 3 secondary bronchial buds on right, 2 on left • Secondary bronchial buds give rise to the lung lobes

4. Pseudoglandular Stage6 to 16 weeks • During 6th week: more variable round of branching leading to 10 tertiary bronchi • Tertiary bronchi become the bronchopulmonary segments • By week 16: 14 successive branchings have occurred producing the terminal bronchioles

5. Canalicular Stage16 to 28 weeks • Each terminal bronchiole divides into 2 or more respiratory bronchioles • These branches progress in a craniocaudal direction • Mesodermal tissue surrounding these structures become highly vascularized, presumably via angiogenesis • Blood vessels begin to come closely apposed to lung epithelium • Lung epithelium begins to differentiate into specialized cell types

6. Saccular Stage28 to 36 weeks • By week 36, the first formed terminal branches are invested in a rich capillary network forming terminal sacs or primitive alveoli • Only about 5% to 20% of all terminal sacs are formed before birth • Terminal sacs continue to be formed well into childhood • Form and differentiate in craniocaudal progression • Process mostly complete by age 2 years

7. Alveolar Stage36 weeks to Term (and beyond) • Continued maturation of terminal sacs into mature alveoli • Septation is the process in which alveoli are further subdivided occurs after birth • About 20 to 70 million terminal sacs in each lung before birth, 300 to 400 million alveoli in each mature lung • Each septum contains smooth muscle and capillaries

8. Additional Considerations • Lung a composite of endodermal and mesodermal tissues • Implications for inflammation, repair, and neoplasia

9. Clinical CorrelationDevelopmental Abnormalities • Pulmonary hypoplasia or agenesis • Tracheoesophageal fistula and esophageal atresia • Foregut cysts • Pulmonary sequestrations

10. Clinical CorrelationNeonatal Respiratory Distress Syndrome • Immaturity of the lungs • Deficiency of pulmonary surfactant

11. Research IssuesApproaches for Studying Lung Development • Organ Culture • Transgenic and Gene-Targeting Techniques • Engineered loss-of-function mutations (knock-outs) and gain-of-function transgene mutations • Identification of important transcription factors • Models of human pulmonary disease • Molecular and Cellular Models • Demonstrate that branching morphogenesis is regulated by reciprocal interaction between the endoderm and mesoderm • Components of ECM and growth factors and their receptors • Expression in cell-specific and time-specific contexts • Genes regulating differentiation of specialized cell types