Developmental Therapeutics for Alveolar Generation and Regeneration: Implications for Bronchopulmonary Dysplasia and Prematurity-Associated Lung Disease

The mechanisms by which alveoli form during lung development remain under investigation. The classical model proposes formation through secondary septation, whereas an alternative proposed model suggests that alveoli arise through epithelial budding within preformed mesenchymal stabilizing rings. Regardless of the precise morphogenetic mechanism, alveolar formation depends on coordinated interactions among epithelial progenitor cells, pulmonary endothelial cells, mesenchymal populations, extracellular matrix remodeling, and biomechanical forces. Stereologic imaging supports continued postnatal alveolar formation and the biological plausibility of alveolar regeneration. These observations are relevant to bronchopulmonary dysplasia (BPD), a disorder of interrupted alveolar and pulmonary vascular development after extremely preterm birth. This review integrates competing morphogenetic models with complementary local and systemic therapeutic concepts. Insulin-like growth factor 1 (IGF-1) provides systemic and local support for alveolar, vascular, and multiorgan maturation. In contrast, fibroblast growth factor 10 (FGF10) is a major local morphogen that regulates epithelial branching, alveolar induction, and repair. Physiologic IGF-1 replacement is being evaluated clinically to reduce BPD severity; FGF10-mediated regeneration remains at the preclinical proof-of-concept stage. Together, these pathways illustrate how preserving or resuming developmental signaling may support lifelong lung health after extremely preterm birth.