Chronic ethanol: mitochondrial dysfunction and apoptosis

慢性乙醇：线粒体功能障碍和细胞凋亡

• 批准号: 7490451
• 负责人: Lou Ann S Brown
• 金额: $ 33.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490451
• 关键词: AGTR2 gene; Acetaldehyde; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Alcohol abuse; Alcohol consumption; Alcohols; Alveolar; Animal Model; Antioxidants; Apoptosis; Apoptotic; Award; Biology; Blood capillaries; Cell Death; Cell physiology; Cells; Cholesterol; Chronic; Coupled; Defect; Deposition; Development; Drug Metabolic Detoxication; Endoplasmic Reticulum; Endotoxemia; Endotoxins; Epithelial; Ethanol; Functional disorder; Generations; Glutathione; Goals; In Vitro; Inflammatory; Injury; Laboratories; Link; Liquid substance; Lung; Mediating; Mediator of activation protein; Mitochondria; Multi-Institutional Clinical Trial; Newborn Respiratory Distress Syndrome; Oxidants; Oxidative Stress; Pathway interactions; Patients; Phenotype; Publishing; Relative Risks; Research Personnel; Risk; Role; Sepsis; Septic Shock; Series; Stress; alcohol effect; capillary; chronic alcohol ingestion; in vivo; member; mitochondrial dysfunction; mitochondrial membrane; novel; problem drinker; programs; prospective; response; surfactant; uptake

DESCRIPTION (provided by applicant): In a prospective multi-center clinical study of septic shock patients, alcoholic subjects represented about 50% of the subjects who developed the Acute Respiratory Distress Syndrome (ARDS). The relative risk in alcoholic patients was 3.7 to 1, making it the single most important factor that influenced the development of ARDS. In otherwise healthy alcoholics, the concentration of the critical antioxidant glutathione (GSH) was decreased by 80% suggesting chronic oxidant stress in the alveolar space. In animal models, we have demonstrated that chronic ethanol ingestion results in diverse pulmonary abnormalities including chronic oxidative stress, alveolar-capillary barrier dysfunction, and exaggerated endotoxin-mediated acute lung injury. In the alveolar type II (AT2) cell, chronic ethanol ingestion impairs mitochondrial GSH uptake. This decrease in mitochondrial GSH in the AT2 cell was coupled with decreased mitochondrial membrane integrity, decreased availability of ATP, and increased risk of apoptosis in response to a in vitro or in vivo second hit GSH availability in the mitochondria is key to the ethanol-induced risk of acute lung injury as demonstrated by the capacity of GSH precursors to restore mitochondrial GSH, restore mitochondria integrity, restore AT2 cell function and to decrease the risk of AT2 cell death during endotoxemia. Recent new findings suggest that chronic ethanol promotes endoplasmic reticulum stress and cholesterol loading of the mitochondrial membrane. These effects of ethanol on mitochondrial GSH depletion could be blocked by agents known to inhibit endoplasmic reticulum stress or inhibit cholesterol synthesis. This competitive renewal will examine the novel hypothesis that ethanol-induced endoplasmic reticulum stress in AT2 cells drives mitochondrial GSH depletion and, subsequent mitochondrial stress. Thus, chronic ethanol ingestion upregulates two intrinsic cell death pathways, endoplasmic reticulum stress and mitochondrial stress, that primes the AT2 cell for accelerated apoptosis in response to a second hit. The aims are as follows: 1) Determine the mechanisms by which chronic ethanol ingestion upregulates two apoptotic pathways in AT2 cells with a particular focus on the role of acetaldehyde as a critical mediator. 2) Determine whether or not ethanol-induced ER stress drives the mitochondrial stress that characterizes the alcoholic AT2 cell. 3) Determine if strategies to relieve ER stress will rescue the alcoholic AT2 cell from its pro-apoptotic phenotype. 4) Determine if relief of ER stress will rescue AT2 cell apoptosis in the alcoholic lung during endotoxemia.

描述（由申请人提供）：在对败血性休克患者的前瞻性多中心临床研究中，酒精受试者约占发展急性呼吸遇险综合征（ARDS）的受试者的50％。酒精患者的相对风险为3.7比1，使其成为影响ARDS发展的最重要因素。在其他健康的酒精中毒中，临界抗氧化剂谷胱甘肽（GSH）的浓度降低了80％，表明肺泡空间中的慢性氧化应激。在动物模型中，我们已经证明，慢性乙醇摄入会导致多种肺部异常，包括慢性氧化应激，肺泡毛细血管屏障功能障碍以及夸张的内毒素介导的急性肺损伤。在肺泡II型（AT2）细胞中，慢性乙醇摄入会损害线粒体GSH的摄取。 AT2细胞中线粒体GSH的这种下降与线粒体膜完整性的降低相结合，ATP的可用性降低，响应于体外或体内第二次命中率的凋亡风险增加，线粒体对乙醇诱导的急性肺部受伤的关键，这是对乙醇诱发的急性造成的肌肉损伤的关键。 GSH，恢复线粒体完整性，恢复AT2细胞功能并降低内肌毒素血症期间AT2细胞死亡的风险。最近的新发现表明，慢性乙醇会促进线粒体膜的内质网应激和胆固醇载荷。乙醇对线粒体GSH耗竭的影响可能会被已知抑制内质网应激或抑制胆固醇合成的药物所阻断。这种竞争性更新将研究以乙醇诱导的AT2细胞中乙醇诱导的内质网应激的新假设，可驱动线粒体GSH耗竭以及随后的线粒体应激。因此，慢性乙醇摄入升上了两种固有的细胞死亡途径，内质网应激和线粒体胁迫，这些应激质量是AT2细胞加速凋亡，以响应第二次击中。目的如下：1）确定慢性乙醇在AT2细胞中上调两种凋亡途径的机制，特别关注乙醛作为关键介体的作用。 2）确定乙醇诱导的ER应力是否驱动了含酒精AT2细胞的线粒体应力。 3）确定缓解ER应力的策略是否会从其促凋亡表型中拯救酒精AT2细胞。 4）确定在内毒素血症期间，在酒精性肺中，ER应力缓解是否会挽救AT2细胞凋亡。