Metabolic mechanisms of impaired vascularization during hyperoxic lung injury

支气管肺发育不良（BPD）是一种慢性肺部疾病，其特征是肺泡发育不良， 血管化受损。BPD在临床上的定义是持续依赖于补充氧气超过 早产儿矫正妊娠36周。虽然大多数BPD幸存者可以断奶， 补充氧气，可能会有残留的肺功能障碍和心血管后遗症，在青春期 和成年。氧气补充可以破坏正常的肺发育， 微血管（血管发芽）。血管生长与内皮细胞的代谢状态密切相关 (ECs)糖酵解和线粒体脂肪酸氧化（FAO）是EC增殖所必需的， 血管发芽。尚不清楚高氧暴露引起的肺EC代谢改变是否损害 血管化、肺泡发育不良和随后的肺损伤。我们的初步数据显示 暴露降低肺EC的线粒体呼吸，特别是增加肺EC的FAO和FA摄取， EC。然而，当这些细胞在高氧暴露后在空气中恢复时，增加的FAO减少， 尽管FATP 5基因表达持续增加，促进FA摄取。这与增加 肺内皮细胞对高氧反应的凋亡，随后空气恢复。这些观察提示 高氧后空气恢复导致FA摄取/氧化失衡，导致FA蓄积， 细胞凋亡，可能是由于神经酰胺合成增加。凋亡和增殖之间的不平衡 在BPD的血管化和肺泡化受损中起重要作用。初步数据显示， L-卡尼汀增强FAO可减弱高氧诱导的小鼠肺内皮细胞凋亡。相反地， 通过特异性肉毒碱棕榈酰转移酶1抑制剂etomoxir抑制FAO， 这些细胞的凋亡。两种处理均不影响肺EC增殖。BPD的肺部病理学可以是 在新生儿时暴露于高氧的啮齿动物中模仿。我们进一步表明，L-肉毒碱衰减，而 依托莫西加重了新生小鼠中高氧诱导的肺泡简化。因此，我们假设， 高氧暴露导致FA积累，而提高FAO可保护免受高氧诱导的肺损伤 新生儿内皮细胞凋亡及随后受损的血管化和肺泡化。我们建议：1） 确定高氧诱导的肺EC中FAO初始增加的潜在机制; 2）确定如何 FAO调节高氧暴露时肺EC凋亡; 3）确定FAO在高氧暴露中的作用。 诱导新生小鼠血管化和肺泡化受损。这项工作将揭示新的代谢 高氧诱导的肺血管化和肺泡化损伤的机制。反过来，这将 在药理学和分子方法的开发中具有显著的转化潜力 靶向脂肪酸催化剂，以改善BPD的肺损伤和心血管后遗症。

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.