Therapeutic targeting of oxidative-inflammatory crosstalk by Apelin-12 in neonatal hyperoxia-induced lung injury

Hyperoxia-induced neonatal acute lung injury (ALI) constitutes a significant clinical challenge with limited therapeutic options. This study investigates the protective role of Apelin-12, an endogenous peptide, in a neonatal mouse model of hyperoxia-induced ALI. We demonstrate that hyperoxia exposure significantly reduces serum and pulmonary Apelin-12 levels and downregulates APJ receptor expression. Administration of Apelin-12 (15 μg/kg) markedly attenuated lung injury, evidenced by improved lung function (restored peak expiratory flow, reduced airway resistance, enhanced dynamic compliance), decreased pathological damage (lower lung injury score, reduced wet/dry ratio), and diminished neutrophil infiltration (suppressed myeloperoxidase activity). Apelin-12 significantly mitigated oxidative stress by lowering malondialdehyde levels while restoring superoxide dismutase activity and glutathione content. Furthermore, it reduced inflammatory cell counts and protein leakage in bronchoalveolar lavage fluid (BALF), along with suppressing IL-1β and IL-18 cytokine release. Mechanistically, Apelin-12 activated the Nrf2/HO-1 antioxidant pathway and inhibited NF-κB signaling. Notably, hyperoxia paradoxically suppressed NLRP1 inflammasome components (NLRP1, ASC, Caspase-1) at mRNA and protein levels, which were restored by Apelin-12 treatment. These results indicate that Apelin-12 protects against hyperoxic neonatal ALI by alleviating oxidative stress, inflammation, and lung dysfunction through coordinated modulation of the NLRP1 inflammasome, Nrf2/HO-1, and NF-κB pathways, highlighting its therapeutic potential for neonatal lung injury.