Bronchopulmonary dysplasia (BPD) is a chronic lung disease, which is characterized by alveolar dysplasia and impaired vascularization. BPD is defined clinically by continued dependency on supplemental oxygen beyond 36 weeks corrected gestation in premature infants. Although most BPD survivors can be weaned from supplemental oxygen, there can be residual pulmonary dysfunction and cardiovascular sequelae in adolescence and adulthood. Oxygen supplementation can disrupt normal lung development and blunt the growth of pulmonary microvasculature (vessel sprouting). Blood vessel growth is tightly linked to metabolic status in endothelial cells (ECs); with both glycolysis and mitochondrial fatty acid oxidation (FAO) being essential for EC proliferation and vessel sprouting. It is not known whether alteration in lung EC metabolism caused by hyperoxic exposure impairs vascularization, alveolar dysplasia, and subsequent lung injury. Our preliminary data show that hyperoxic exposure reduced mitochondrial respiration in lung ECs and specifically increased FAO and FA uptake in lung ECs. However, the increased FAO was reduced when these cells were recovered in air after hyperoxic exposure, despite continued increase in FATP5 gene expression, facilitating FA uptake. This was associated with increased apoptosis in lung ECs in response to hyperoxia followed by air recovery. These observations suggest that hyperoxia followed by air recovery causes a FA uptake/oxidation imbalance, leading to FA accumulation and apoptosis, perhaps due to increased ceramide synthesis. Imbalance between apoptosis and proliferation plays an important role in impaired vascularization and alveolarization in BPD. Our preliminary data show that enhancing FAO by L-carnitine attenuated hyperoxia-induced apoptosis in mouse lung ECs. Conversely, inhibiting FAO by a specific carnitine palmitoyltransferase 1 inhibitor, etomoxir, increased hyperoxia-induced apoptosis in these cells. Neither treatment affected lung EC proliferation. The lung pathology of BPD can be mimicked in rodents exposed to hyperoxia as neonates. We further show that L-carnitine attenuated, whereas etomoxir aggravated, hyperoxia-induced simplification of the alveoli in neonatal mice. Thus, we hypothesize that hyperoxic exposure causes FA accumulation, whereas enhancing FAO protects against hyperoxia-induced lung EC apoptosis and subsequent impaired vascularization and alveolarization in neonates. We propose to: 1) determine the mechanisms underlying hyperoxia-induced initial increases in FAO in lung ECs; 2) determine how FAO modulates lung EC apoptosis in response to hyperoxic exposure; 3) determine the role of FAO in hyperoxia- induced impaired vascularization and alveolarization in neonatal mice. The work will uncover novel metabolic mechanisms for hyperoxia-induced impairment of pulmonary vascularization and alveolarization. In turn, this will have a significant translational potential in the development of pharmacological and molecular approaches targeting fatty acid catabolism to ameliorate lung injury and cardiovascular sequelae in BPD.
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