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

基本信息

批准号：
10200078
负责人：
Hongwei Yao
金额：
$ 26.16万
依托单位：
OCEAN STATE RESEARCH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
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/10200078
关键词：
Adolescence Adult Affect Agreement Air Alveolar 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/antagonist knock-down lipid metabolism lung development lung injury neonatal mice neonate novel oxidation pulmonary function response sensor supplemental oxygen uptake

项目摘要

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）是一种慢性肺部疾病，其特征是肺泡发育不良和血管形成受损。 BPD是通过持续依赖对补充氧气的临床定义的 36周纠正了早产婴儿的妊娠。尽管大多数BPD幸存者可以从中断奶补充氧气，青春期可能存在残留的肺功能障碍和心血管后遗症和成年。补充氧气会破坏正常的肺发育和钝性肺的生长微脉管系统（血管发芽）。血管生长与内皮细胞中的代谢状态紧密相关（ECS）;糖酵解和线粒体脂肪酸氧化（FAO）均对EC增殖至关重要船只发芽。尚不清楚肺EC代谢的改变是否由高氧气暴露损害引起血管形成，肺泡发育不良和随后的肺损伤。我们的初步数据表明高氧暴露于肺EC中的线粒体呼吸减少，并特别增加了肺中的粮农组织和FA摄取 ECS。然而，当高氧化后在空气中回收这些细胞时，增加的粮农组织减少了，尽管FATP5基因表达持续增加，但促进了FA的吸收。这与增加有关肺EC中的凋亡对高氧，然后是空气回收。这些观察表明高氧之后，空气恢复会导致FA摄取/氧化失衡，导致FA积累和凋亡，可能是由于神经酰胺的合成增加所致。细胞凋亡与增殖玩法之间的不平衡 BPD中血管化和肺泡化受损中的重要作用。我们的初步数据表明通过L-肉碱衰减的高氧诱导的小鼠肺ECS的凋亡增强粮农组织。反过来，通过特定的肉碱棕榈转移酶1抑制剂抑制粮农组织，etomoxir增加了高氧诱导的这些细胞的凋亡。两项治疗都不影响肺EC的增殖。 BPD的肺病理可能是模仿暴露于高氧作为新生儿的啮齿动物。我们进一步表明，L-肉碱减弱，而 Etomoxir加重，高氧诱导的新生小鼠肺泡的简化。因此，我们假设高氧气暴露会导致FA积累，而增强的粮农 EC凋亡以及随后的新生儿血管化和肺泡化受损。我们建议：1）确定肺ECS中粮农组织的初始增加的基础机制； 2）确定如何粮农组织可调节肺EC凋亡，以应对高氧的暴露； 3）确定粮农组织在高氧中的作用 - 在新生小鼠中诱导的血管化和牙槽化受损。这项工作将发现新代谢高氧引起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发展中具有巨大的翻译潜力靶向脂肪酸分解代谢可改善BPD中的肺损伤和心血管后遗症。