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In neonates, hyperoxia or positive pressure ventilation causes continued lung injury characterized by simplified vascularization and alveolarization, which are the hallmarks of bronchopulmonary dysplasia. Although endothelial cells (ECs) have metabolic flexibility to maintain cell function under stress, it is unknown whether hyperoxia causes metabolic dysregulation in ECs, leading to lung injury. We hypothesized that hyperoxia alters EC metabolism, which causes EC dysfunction and lung injury. To test this hypothesis, we exposed lung ECs to hyperoxia (95% O 2 /5% CO 2 ) followed by air recovery (O 2 /rec). We found that O 2 /rec reduced mitochondrial oxidative phosphorylation without affecting mitochondrial DNA copy number or mitochondrial mass and that it specifically decreased fatty acid oxidation (FAO) in ECs. This was associated with increased ceramide synthesis and apoptosis. Genetic deletion of carnitine palmitoyltransferase 1a (Cpt1a), a rate-limiting enzyme for carnitine shuttle, further augmented O 2 /rec-induced apoptosis. O 2 /rec-induced ceramide synthesis and apoptosis were attenuated when the FAO was enhanced by l-carnitine. Newborn mice were exposed to hyperoxia (&gt;95% O 2 ) between Postnatal Days 1 and 4 and were administered l-carnitine (150 and 300 mg/kg, i.p.) or etomoxir, a specific Cpt1 inhibitor (30 mg/kg, i.p.), daily between Postnatal Days 10 and 14. Etomoxir aggravated O 2 /rec-induced apoptosis and simplified alveolarization and vascularization in mouse lungs. Similarly, arrested alveolarization and reduced vessel numbers were further augmented in EC-specific Cpt1a -knockout mice compared with wild-type littermates in response to O 2 /rec. Treatment with l-carnitine (300 mg/kg) attenuated O 2 /rec-induced lung injury, including simplified alveolarization and decreased vessel numbers. Altogether, enhancing FAO protects against hyperoxia-induced EC apoptosis and lung injury in neonates.

Fatty Acid Oxidation Protects against Hyperoxia-induced Endothelial Cell Apoptosis and Lung Injury in Neonatal Mice