You’re Only An
Embryo Once
Review of Development of the
Respiratory System
Embryonic Stage
22 days to 6 weeks
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Day 22: Formation of a ventral outpouching from the
endodermal foregut—respiratory diverticulum
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Grows ventrocaudally through mesenchyme around the
foregut
Days 26-28: First bifurcation—primary bronchial
buds which give rise to the right and left lungs
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Proximal end of diverticulum forms the trachea and larynx
Glottis forms at the original point of the diverticulum
Embryonic Stage
22 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
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Pseudoglandular Stage
6 to 16 weeks

During 6th week: more variable round of
branching leading to 10 tertiary bronchi
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Tertiary bronchi become the bronchopulmonary
segments
By week 16: 14 successive branchings have
occurred producing the terminal bronchioles
Canalicular Stage
16 to 28 weeks
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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
Saccular Stage
28 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

Alveolar Stage
36 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

Additional Considerations

Lung a composite of endodermal and
mesodermal tissues
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Implications for inflammation, repair, and neoplasia
Clinical Correlation
Developmental Abnormalities
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Pulmonary hypoplasia or agenesis
Tracheoesophageal fistula and esophageal atresia
Foregut cysts
Pulmonary sequestrations
Clinical Correlation
Neonatal Respiratory Distress Syndrome
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Immaturity of the lungs
Deficiency of pulmonary surfactant
Research Issues
Approaches for Studying Lung Development
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Organ Culture
Transgenic and Gene-Targeting Techniques
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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
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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