The Postnatal Lung Maturation Disrupted by Increased Pulmonary Blood Flow and Its Clinical Implications

BACKGROUND: Increased pulmonary blood flow (IPF) from congenital heart diseases causes pediatric pulmonary hypertension and respiratory distress, yet its impact on postnatal lung maturation remains unknown. OBJECTIVES: This study aimed to establish a neonatal model of IPF and elucidate the molecular mechanisms underlying impaired lung maturation, thereby identifying potential therapeutic targets. METHODS: Neonatal mice underwent surgical creation of an aortocaval fistula to induce IPF. Bulk RNA sequencing compared lung transcriptomes at postnatal day (P)14 (alveolar stage) and P30 (maturity) in IPF vs sham-operated controls. Histological validation was performed, and the effects of immunosuppression (cyclosporine A) were assessed. RESULTS: IPF generated 2,272 differentially expressed genes vs 943 in controls, revealing the following: 1) shared downregulation of extracellular matrix organization and cell cycle pathways; 2) IPF-specific cell cycle dysregulation (downregulated Birc5/CENPE) and hyperactive immunity (upregulated NLRP3/IL23R) impairing alveolar/capillary development; 3) suppressed circadian (Per2) and neural pathways (Nr1d1) unique to normal maturation. Cyclosporine A treatment mitigated alveolar simplification, attenuated vascular remodeling, and improved alveolar epithelial differentiation. CONCLUSIONS: This study establishes the first neonatal IPF model and identifies actionable therapeutic targets, including immune modulators (NLRP3/IL23R inhibitors), cell cycle regulators (Birc5/CENPE agonists), and neural/circadian mediators (Nr1d1/Per2 activators). These findings provide a roadmap for mitigating IPF-driven lung maldevelopment.