Metabolic mechanisms of impaired vascularization during hyperoxic lung injury

高氧性肺损伤期间血管化受损的代谢机制

• 批准号: 10437831
• 负责人: Hongwei Yao
• 金额: $ 28.47万
• 依托单位: OCEAN STATE RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437831
• 关键词: Adolescence; Adult; Affect; Agreement; Air; Alveolar; Alveolus; Apoptosis; Attenuated; Automobile Driving; Biology; Blood Vessels; Bronchopulmonary Dysplasia; Cardiopulmonary; Cardiovascular system; Carnitine Palmitoyltransferase I; Carrier Proteins; Catabolism; Cell Proliferation; Cells; Cellular Metabolic Process; Centers of Research Excellence; Ceramides; Chronic lung disease; Clinical; Cytosol; Data; Dependence; Development; Dysplasia; Endothelial Cells; Exposure to; Fatty Acids; Fetal Development; Functional disorder; Gene Expression; Glycolysis; Growth; Growth and Development function; Hyperoxia; Impairment; Knockout Mice; Lead; Levocarnitine; Link; Lipids; Lung; Mediating; Messenger RNA; Metabolic; Mitochondria; Molecular; Mus; Neonatal; Oxygen; PPAR gamma; Patients; Pharmacological Treatment; Pharmacology; Play; Pregnancy; Premature Infant; Pulmonary Pathology; Recovery; Residual state; Respiration; Rodent; Rodent Model; Role; Sphingolipids; Supplementation; Survivors; Testing; Up-Regulation; Vascularization; Weaning; Work; angiogenesis; blood vessel development; capillary bed; etomoxir; fatty acid oxidation; inhibitor; knock-down; lipid metabolism; lung development; lung injury; neonatal mice; neonate; novel; oxidation; pulmonary function; pulmonary vascular disorder; response; sensor; supplemental oxygen; translational potential; uptake

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.

支气管肺发育不良(BPD)是一种以肺泡发育不良为特征的慢性肺部疾病。 血管形成受损。BPD的临床定义是对补充氧气的持续依赖 早产儿36周矫正妊娠。尽管大多数BPD幸存者可以断奶 补充氧气，青春期可能会有残留的肺功能障碍和心血管后遗症 和成人期。氧气补充会扰乱肺的正常发育，阻碍肺的生长。 微血管系统(血管萌发)。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)对EC增殖和 导管正在萌芽。高氧暴露引起的肺内皮细胞代谢的改变是否会损害尚不清楚 血管形成、肺泡发育不良和随后的肺损伤。我们的初步数据显示，高氧症 暴露使肺内皮细胞线粒体呼吸减少，并特别增加了肺对FAO和FA的摄取 ECS。然而，当这些细胞在高氧暴露后被恢复到空气中时，增加的FAO减少， 尽管FATP5基因表达持续增加，促进了FA的摄取。这与增加的 肺内皮细胞对高氧和空气恢复的反应中的细胞凋亡。这些观察结果表明 高氧后空气恢复导致FA摄取/氧化失衡，导致FA积聚和 细胞凋亡，可能是由于神经酰胺合成增加。细胞凋亡与增殖之间的失衡作用 BPD中血管和肺泡化受损的重要作用。我们的初步数据显示， L肉碱增强粮农组织减轻高氧诱导的小鼠肺内皮细胞凋亡。相反， 肉碱棕榈酰转移酶1的特异性抑制剂etomoxir抑制FAO增加高氧诱导 这些细胞中的细胞凋亡。两种治疗方法均不影响肺内皮细胞增殖。BPD的肺病理可以是 在刚出生时暴露在高氧环境中的啮齿类动物身上模拟。我们进一步证明L-卡尼汀有减弱的作用，而 依托莫司加重高氧诱导的新生小鼠肺泡的简化。因此，我们假设 高氧暴露导致FA积聚，而增强FAO预防高氧诱导的肺 新生儿中内皮细胞凋亡和随后的血管和肺泡化受损。我们建议：1) 确定高氧导致粮农组织肺内皮细胞初始增加的机制；2)确定如何 粮农组织调节肺内皮细胞凋亡以应对高氧暴露；3)确定粮农组织在高氧中的作用- 诱导新生小鼠血管和肺泡化受损。这项工作将揭示新的新陈代谢 高氧致肺血管和肺泡化损伤的机制。反过来，这将是 在药理学和分子方法的开发中具有显著的翻译潜力 以脂肪酸分解代谢为靶点改善BPD的肺损伤和心血管后遗症。