ETHANOL RESULTS IN OXIDANT DEPENDENT TISSUE INJURY

乙醇导致氧化依赖性组织损伤

• 批准号: 2693513
• 负责人: DALE A PARKS
• 金额: $ 22.02万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2693513
• 关键词: ascorbate; azo compounds; enzyme activity; ethanol; glutathione; high performance liquid chromatography; laboratory mouse; myoglobin; nitrates; nitric oxide; nitric oxide synthase; oxidative stress; oxidized lipid; superoxides; tocopherols

DESCRIPTION: (Adapted from the Investigator's Abstract) Chronic alcoholism is a major health problem in the U.S. resulting in over $12 billion dollars in medical expenses each year. Alcohol-induced hepatic damage is responsible for the majority of the morbidity and mortality associated with chronic alcohol consumption. Liver cirrhosis ranks as the 6th most common cause of death in the U.S., with ethanol implicated as the causative etiologic agent in 41-95 percent of the cases. The disease progresses from fatty infiltration and inflammation to irreversible tissue damage, with liver transplantation ultimately the only recourse. Although chronic alcohol consumption results primarily in hepatic dysfunction, there are also strong links to vascular (stroke, hypertension) and pulmonary (acute respiratory distress syndrome) complications. Chronic ethanol consumption has been linked to increased production of reactive oxygen and nitrogen species and compromised antioxidant defense systems. However, there are no studies which systematically integrate the effects of chronic ethanol consumption to the generation of reactive radical species, nitration of purines, proteins and lipids, and the consequent alterations in hepatic, pulmonary, and vascular structure/function. The investigators hypothesize that chronic ethanol administration increases nitric oxide ( NO), superoxide (02-), and peroxynitrite (ONOO-) production, thus leading to nitration and oxidation of biomolecules and compromised tissue structure/function. They propose to utilize genetically defined mouse models to modulate oxidant generating enzymes (iNOS and AO/XO) and antioxidant defenses (CuZn SOD1) to gain mechanistic insight into the ethanol-induced nitration of biomolecules and alterations in vascular and tissue structure/function. The investigators will ultimately apply targeted pharmacological interventions to minimize the ethanol-induced injury. Specific Aims: 1. Define the contribution of NO, O2-, and ONOO- in nitration of biomolecules (purines, proteins and lipids) and impaired tissue and vascular structure/function following chronic ethanol administration. 2. Modulate NO and 02- production to (a) reveal mechanisms of oxidative injury to liver, lung and vasculature, and (b) attenuate tissue and vascular dysfunction associated with chronic ethanol consumption. 3. Utilize targeted pharmacologic interventions to minimize chronic ethanol-induced nitration of biomolecules (purine, protein, and lipid) and subsequent impairment of tissue and vascular structure/function.These observations will provide a foundation for understanding the interactions for understanding the interactions of superoxide with NO in hepatic, pulmonary, and vascular tissue injury resulting from chronic ethanol administration. Mechanistic insights gained from these studies will guide development of pharmacologic interventions to limit the detrimental effects of reactive species and decrease the morbidity and mortality associated with chronic alcohol consumption and serve as a prelude to human clinical trials.

描述：（改编自研究者摘要）慢性酒精中毒 是美国的一个重大健康问题，造成超过 120 亿美元的损失 每年的医疗费用。 酒精引起的肝损伤是 造成与此相关的大部分发病率和死亡率 长期饮酒。 肝硬化位居第六位 美国的死亡原因，乙醇是导致死亡的原因 41-95% 的病例中有病因。 疾病进展自 脂肪浸润和炎症导致不可逆的组织损伤 肝移植最终是唯一的出路。 虽然慢性 饮酒主要导致肝功能障碍，此外还有 与血管（中风、高血压）和肺（急性 呼吸窘迫综合征）并发症。 慢性乙醇消耗 与活性氧和氮的产生增加有关 物种和受损的抗氧化防御系统。 然而，没有 系统整合长期乙醇影响的研究 消耗到反应自由基物种的产生，硝化 嘌呤、蛋白质和脂质，以及随之而来的肝脏变化， 肺和血管结构/功能。 研究人员假设 长期服用乙醇会增加一氧化氮 (NO)、超氧化物 (02-)和过氧亚硝酸盐(ONOO-)的产生，从而导致硝化和 生物分子氧化和组织结构/功能受损。 他们 提议利用基因定义的小鼠模型来调节氧化剂 产生酶（iNOS 和 AO/XO）和抗氧化防御（CuZn SOD1） 深入了解乙醇诱导的生物分子硝化作用 以及血管和组织结构/功能的改变。 这 研究人员最终将应用有针对性的药物干预措施 以尽量减少乙醇引起的损伤。 具体目标： 1. 定义 NO、O2- 和 ONOO- 在生物分子（嘌呤、 蛋白质和脂质）以及受损的组织和血管结构/功能 长期服用乙醇后。 2. 调节NO和02- 生产以（a）揭示肝、肺和肝脏氧化损伤的机制 脉管系统，以及（b）减弱相关的组织和血管功能障碍 长期消耗乙醇。 3. 使用靶向药物 尽量减少长期乙醇引起的生物分子硝化的干预措施 （嘌呤、蛋白质和脂质）以及随后的组织损伤和 血管结构/功能。这些观察将为 理解相互作用 理解相互作用 超氧化物与NO在肝、肺和血管组织损伤中的作用 长期服用乙醇所致。 获得的机制见解 这些研究将指导药物干预措施的开发 限制活性物质的有害影响并降低发病率 和与长期饮酒相关的死亡率，并作为 人体临床试验的前奏。