LAUSR

In neonates, hyperoxia causes lung injury characterized by impaired vascularization and alveolarization. These are the hallmarks of bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants with long-term sequelae. The pulmonary vascular bed is essential for alveolar formation during late stages of lung development. Although endothelial cells (ECs) rely mainly on glycolysis for bioenergetics, they have metabolic flexibility to maintain cell function under stress. It is unknown whether hyperoxia alters EC metabolism and what are the consequences on lung injury and repair. We hypothesize that hyperoxia causes metabolic reprogramming leading to EC dysfunction and lung injury in neonatal mice. We exposed mouse fetal lung EC line and primary lung microvascular ECs from neonatal mice to air (21% O2/5% CO2) and hyperoxia (95% O2/5% CO2). Some cultures were placed in air for 24 h post exposure (air recovery). Hyperoxia reduced mitochondrial respiration in lung ECs as determined by the Seahorse XF24 Analyzer. Interestingly, hyperoxia specifically increased fatty acid oxidation (FAO), which was reduced when lung ECs were recovered in air after hyperoxia. This was associated with increased apoptosis in hyperoxia followed by air recovery. Enhancing FAO by L-carnitine (0.5 mM) reduced whereas inhibiting long-chain FA entry into mitochondria by a carnitine palmitoyltransferase 1 inhibitor (etomoxir, 100 μM) augmented hyperoxia-induced apoptosis. Furthermore, etomoxir (30 mg/kg) aggravated hyperoxia-induced simplification of the alveoli in neonatal mice, which was attenuated by L-carnitine (300 mg/kg). In conclusion, hyperoxia has long-term effects on FAO, which may affect lung EC survival and could lead to impaired vascularization and alveolarization in neonatal lungs. Targeting FAO could be a potential therapeutic approach to ameliorate lung injury in BPD.