Hyperoxia promotes bronchopulmonary dysplasia via Noggin-mediated BMP4 antagonism and cellular senescence.

Abstract

Bronchopulmonary dysplasia (BPD) represents the most prevalent chronic pulmonary complication in preterm infants, with incompletely understood pathophysiological mechanisms. Hyperoxia exposure constitutes a major risk factor for BPD development, inducing cellular senescence that impairs alveolar maturation. While senescence is predominantly mediated by the p53/p21 signaling pathway, upstream regulatory mechanisms remain inadequately defined. This study aimed to identify critical genes through bioinformatics and elucidate the molecular mechanisms by which the Noggin-BMP4 signaling axis mediates cellular senescence in BPD pathogenesis. Integrating BPD transcriptomic datasets with aging-related databases via WGCNA, Noggin was identified as a hub gene linking BPD and cellular senescence (AUC = 0.80). In HPMECs exposed to 85% hyperoxia, Noggin expression increased approximately 2.5-fold (mRNA) and 2.0-fold (protein), while BMP4 decreased to 50% of controls, accompanied by elevated p53 and p21 expression and positive SA-β-gal staining. Noggin silencing restored BMP4 expression and significantly attenuated hyperoxia-induced p53/p21 upregulation, suggesting that Noggin promotes senescence by suppressing BMP4. In a neonatal rat hyperoxia-induced BPD model, alveolar simplification was observed alongside a threefold increase in Noggin mRNA, a reduction of BMP4 to 30% of controls, and elevated p53/p21 at day 14, corroborating the in vitro findings. These findings suggest that hyperoxia upregulates Noggin to antagonize BMP4 signaling, thereby activating p53/p21-mediated senescence and contributing to alveolar developmental arrest. The Noggin-BMP4 axis may represent a potential therapeutic target for BPD.