Epigenetic programming in bronchopulmonary dysplasia: a framework linking early-life exposures to persistent lung...

Bronchopulmonary dysplasia (BPD) is the most common chronic pulmonary complication of extreme prematurity in infants, now understood as a disorder of disrupted lung development rather than acute injury alone. Conventional clinical and functional criteria fail to capture the full heterogeneity of outcomes or the persistence of pulmonary morbidity into adulthood. Epigenetic mechanisms-including DNA methylation, histone modifications, and non-coding RNAs-provide a unifying biological framework linking perinatal exposures to long-term lung dysfunction. In the preterm lung, hyperoxia, inflammation, infection, pharmacologic interventions, and microbiome alterations durably influence gene expression without changing the DNA sequence, contributing to impaired alveolarization, pulmonary vascular growth, antioxidant defenses, immune regulation, and cellular senescence. Hyperoxia, specifically, has been associated with lasting epigenetic changes in redox-sensitive pathways, angiogenic signaling, and cell cycle control, while inflammatory stimuli may establish epigenetic "memory" that is consistent with the persistence of chronic inflammation and defective repair. Collectively, these processes support a model in which epigenetically programmed lung phenotypes may emerge, characterized by reduced pulmonary reserve, accelerated lung aging, and heightened vulnerability to respiratory disease across the lifespan. Although evidence for transgenerational inheritance in humans is limited, inherited susceptibility remains plausible, but unproven. Framing BPD as a disorder of biological memory emphasizes the need for epigenetic biomarkers, longitudinal cohort studies, and targeted preventive or therapeutic strategies to improve lifelong outcomes in survivors. IMPACT: This review reframes Bronchopulmonary Dysplasia as a disorder of developmental programming and biological memory, integrating hyperoxia, inflammation, and pharmacologic exposures within a DOHaD-based epigenetic framework to explain long-term pulmonary and systemic heterogeneity. It synthesizes experimental, translational, and clinical evidence-including redox epigenetics, trained immunity, sex-specific responses, and lung-brain-immune interactions-supporting a model in which early-life exposures shape lifelong respiratory and extra-pulmonary outcomes, while acknowledging that some mechanisms remain unproven. It identifies key translational priorities, including validation of epigenetic biomarkers, longitudinal multi-omics studies, and cautious development of epigenetic therapies, while emphasizing current methodological limitations and remaining evidence gaps.