Stages of Lung Development
Lung development progresses through five distinct, sequential stages: embryonic, pseudoglandular, canalicular, saccular, and alveolar, with the first four occurring prenatally and alveolarization continuing into early childhood. 1, 2
The Five Stages
1. Embryonic Stage
- Timing: First 7 weeks of gestation (up to ~day 49) 1
- Key events: The lung primordium emerges as a diverticulum (outpouching) from the foregut, establishing the basic lung anlage with separate left and right lung buds 1, 3
- Mouse equivalent: Up to Theiler stage 16 (gestational day 10.25-10.5) 4
2. Pseudoglandular Stage
- Timing: 5th to 17th week of gestation 1, 2
- Key events: The lung resembles a tubulo-acinar gland as epithelial tubes sprout and branch repeatedly into surrounding mesenchyme through branching morphogenesis 1, 3
- Critical milestone: By the end of this stage, all prospective conducting airways have been formed and acinar limits are recognizable 1
- Mouse equivalent: Extends to approximately gestational day 16.5 4
3. Canalicular Stage
- Timing: 17th to 26th week of gestation 1, 2
- Key events:
- Clinical significance: By the end of this stage, the first gas exchange becomes possible and survival of premature infants becomes feasible 3
- Mouse equivalent: Gestational day 16.5-17.5 4
4. Saccular Stage
- Timing: 26th week of gestation until birth 1, 2
- Key events:
- Pulmonary parenchyma grows substantially 1
- Connective tissue between airspaces thins 1
- Surfactant system matures further 1, 5
- Type II pneumocytes producing surfactant protein C (Sp-C) are detected 4
- Airspaces present are smooth-walled transitory ducts and saccules with thick primitive septa containing double capillary networks 1
5. Alveolar Stage
- Timing: Begins late in gestation but primarily occurs postnatally during the first 1-3 years of life, continuing into young adulthood 1, 3
- Key events:
- True alveoli are formed through septation, which subdivides existing airspaces by forming new walls 1, 3
- Gas exchange surface area increases dramatically 1
- Primitive septa with double capillary networks undergo complete remodeling into mature slender septa with single-layered capillary networks 1, 3
- This process requires angiogenesis to form the second capillary layer at sites where new septa lift off from preexisting mature septa 3
Clinical Implications
Premature Birth Consequences
- Interruption of normal development: Premature birth disrupts the normal progression through these stages, particularly affecting alveolarization 5, 6
- Bronchopulmonary dysplasia (BPD): Very preterm infants develop "new BPD" characterized by uniformly arrested alveolar development with less severe fibrosis but persistent alveolar simplification 4
- Vulnerability to atelectasis: Newborns and small infants lack collateral ventilation structures (pores of Kohn, Lambert channels), making them especially vulnerable to atelectasis when airways are obstructed 7
Pathophysiological Considerations
- Congenital diaphragmatic hernia: Herniation of abdominal viscera into the thorax during the canalicular (16-26 weeks) and saccular (26-36 weeks) stages directly compresses the developing lung, interrupting normal development and causing pulmonary hypoplasia 8
- Timing determines severity: Earlier disruption of lung development results in more severe pulmonary hypoplasia and worse outcomes 8
Key Regulatory Factors
Physical factors (intrathoracic space, lung liquid volume and pressure, amniotic fluid volume) primarily influence lung growth, while hormonal factors (corticotropin, cortisol, thyroid hormones) regulate biochemical maturation, particularly surfactant production 2, 6