Bronchopulmonary dysplasia and prematurity-associated lung disease: emerging therapies to improve lifelong respiratory outcomes

Survival of extremely preterm infants has improved owing to advances in perinatal and neonatal care. However, bronchopulmonary dysplasia (BPD) has remained unabated, and research into preventive measures for the broader spectrum of prematurity-associated lung disease (PLD) has met with limited success. We summarize emerging therapeutic strategies with the potential to favorably influence the lifelong trajectory of lung health of preterm infants, especially the most immature. This narrative review examines recent preclinical and clinical studies on therapies for BPD prevention, focusing on mechanism-based interventions, biologic strategies, and innovative translational tools. Preclinical evidence converges on actionable targets in alveolarization, inflammatory pathways, redox and mitochondrial homeostasis, vascular and matrix remodeling. Novel molecules and drug-repurposing strategies are being tested in animal models, while patient-derived platforms may enable personalized therapeutic approaches. Mechanism-based approaches are progressing through Phase 1-2 clinical trials; pending efficacy analyses, insulin-like growth factor-1 replacement may become the first pharmacological therapy specifically approved to reduce or attenuate BPD. In parallel, cell-based therapies and extracellular vesicle strategies offer a complementary paradigm, acting through pleiotropic biological reprogramming of the injured lung. Ethical-regulatory complexity and the challenges of standardizing and scaling cell-based and cell-free therapies may limit clinical translation. CONCLUSION: A growing repertoire of therapies for BPD holds promise for modifying early respiratory illness and the long-term burden of PLD. Realizing this potential will benefit from both mechanism-informed combinatorial approaches and pleiotropic strategies, supported by patient-derived translational tools and adequately powered efficacy evaluations. Equally essential are tailored neonatal-first regulatory pathways linking the continuum of BPD to the later respiratory morbidity of PLD, a life-course condition with significant public health relevance beyond the neonatal period. WHAT IS KNOWN: • Bronchopulmonary dysplasia (BPD) is the current clinical and regulatory endpoint for neonatal pulmonary therapies. • BPD definitions capture the most severe manifestations of prematurity-associated lung disease (PLD), a broader continuum of respiratory morbidity reaching into adulthood; attenuating BPD may improve the whole spectrum of PLD. WHAT IS NEW: • Therapies targeting alveolar, inflammatory, oxidative, vascular, and remodeling pathways are in clinical development; pending late-stage trials, IGF-1 replacement may become the first disease-modifying therapy to reduce BPD. • Novel targets, experimental platforms, and repurposed drugs hold promise for precision therapies in preterm infants.