Caffeine Protects Against Hyperoxia-Induced Structural Lung Injury and Restores Alveolar Development in Neonatal Rats.

抄録

In the developing lung, oxidative stress caused by relative hyperoxia constitutes a central pathogenic mechanism of neonatal lung injury resulting in bronchopulmonary dysplasia (BPD). The immature postnatal lung is highly susceptible to oxidative damage due to incomplete antioxidant defenses and ongoing alveolar and vascular maturation. In a postnatal high-oxygen-induced rat model of BPD-associated lung injury, three or five days of exposure to 80% oxygen was found to disrupt developmental signaling pathways, downregulating genes essential for alveolarization and angiogenesis while inducing profibrotic mediators and collagen expression (Sirius Red staining). These changes resulted in simplified alveolar architecture, as quantified by toluidine blue staining and mean linear intercept analysis of normalized volumes of parenchyma, non-parenchyma, airspaces, septa, and edema. Acting as a multifunctional antioxidant with antifibrotic activity, caffeine mitigated structural lung damage and normalized the transcription of angiogenic and fibrotic genes. It counteracted TGF-β/CTGF-driven fibrogenic signaling and promoted recovery of normal lung morphology following hyperoxic injury. Under normoxic conditions, however, caffeine transiently upregulated profibrotic mediators. Overall, caffeine mitigates hyperoxia-induced lung injury and may actively promote physiological lung maturation, warranting future studies to define optimal dosing windows, clarify context-dependent fibrotic signaling, and translate gene-level effects into long-term clinical outcomes.