Inhibition of mitochondrial integrated stress response ameliorates ibuprofen-induced endothelial dysfunction in neonatal hyperoxia-induced lung injury

Ibuprofen is a nonsteroidal anti-inflammatory drug with promising activity against patent ductus arteriosus (PDA) in premature infants, but its adverse effect on angiogenesis has hampered the clinical benefit and contributed to development of bronchopulmonary dysplasia (BPD). However, the molecular mechanisms underlying its anti-angiogenic effect have remained incompletely understood. Here we show that ibuprofen compromised mitochondrial function in human endothelial cells, and when used in combination with oxygen therapy-the life-saving respiratory support that preterm infants rely on, ibuprofen and hyperoxia cooperated to activate a heightened mitochondrial integrated stress response (ISR) which resulted in mitochondrial dysfunction and subsequent endothelial defect. In contrast, human endothelial cells pretreated with ISR inhibitor (ISRIB) show significantly enhanced mitochondrial bioenergetics and improved endothelial angiogenic capacity following combination treatment of ibuprofen and hyperoxia. Furthermore, prophylactic ISRIB treatment in vivo reduced ISR signaling in lung endothelial cells and partially improved angiogenesis in ibuprofen-treated BPD mouse lungs. Our findings demonstrate the prophylactic effectiveness of ISRIB against pathologic ISR in driving endothelial dysfunction, thus offering an attractive preventive approach for PDA patients undergoing treatment with ibuprofen and hyperoxia.