Pathogenesis of bronchopulmonary dysplasia: an immunological perspective

Bronchopulmonary dysplasia (BPD), the most common chronic lung disease of prematurity, is at its mechanistic core an immune-developmental disease in which inflammatory injury disrupts normal lung maturation. In the United States, BPD remains among the most common morbidities of very preterm birth, affecting a substantial proportion of infants born before 32 weeks’ gestation. These infants are born before alveolarization is complete, into an inflammatory environment that can impair ongoing lung development. This review advances a single thesis: the heterogeneous prenatal and postnatal insults that precede BPD (chorioamnionitis and the fetal inflammatory response syndrome, Ureaplasma colonization, hyperoxia, mechanical ventilation, sepsis, and intestinal dysbiosis) converge on a small number of innate sensing pathways, principally TLR2 and TLR4 signaling through NF-κB to the NLRP3 inflammasome — with parallel sterile inputs (mitochondrial reactive oxygen species and additional pattern-recognition receptors) feeding the same inflammasome node. We argue that this convergence is what separates BPD from ordinary neonatal lung injury, and that the outcome depends less on the magnitude of the initiating injurious hits than on failure of the resolution program that should terminate them — a hypothesis supported by convergent preclinical evidence but not yet established in preterm infants. Evidence is assembled across three domains: the cellular substrate (M1-skewed, classically activated–like alveolar macrophages, NETs, Th17/Treg imbalance, deficient transplacental IgG transfer); the mediator network (IL-1β, IL-6, IL-8, TNF-α, and the loss of endogenous brakes — specialized pro-resolving mediators, IL-37, Nrf2, short-chain fatty acids); and the signaling architecture (NF-κB, the NLRP3 inflammasome, and trained immunity). We also discuss the mechanistically supported, druggable nodes and the developmental phase in which each is engageable.