ETHANOL RESULTS IN OXIDANT DEPENDENT TISSUE INJURY

描述：(改编自《调查者摘要》)慢性酒精中毒 是美国的一个主要健康问题，导致超过120亿美元 每年的医疗费用。酒精性肝损伤是 对与以下疾病相关的大部分发病率和死亡率负责 长期饮酒。肝硬变排在最常见的第六位。 美国的死因，与酒精有关 致病因素占41%-95%。这种疾病是从 脂肪渗透和炎症导致不可逆的组织损伤， 肝移植最终是唯一的途径。虽然慢性 饮酒主要导致肝功能障碍，还有 与血管(中风、高血压)和肺(急性 呼吸窘迫综合征)并发症。慢性乙醇消费 与活性氧和氮气的产生增加有关 物种和受损的抗氧化防御系统。然而，没有 系统整合慢性酒精影响的研究 消耗到活性自由基物种的生成，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。调查人员的假设是 长期服用乙醇会增加一氧化氮(NO)、超氧化物 (02-)和过亚硝酸根(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 建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)和抗氧化剂防御(CuZn SOD1)以 从机理上深入了解乙醇诱导的生物分子硝化 以及血管和组织结构/功能的改变。这个 研究人员最终将应用有针对性的药物干预 将酒精所致的损伤降至最低。具体目标：1.明确 NO、O2-和ONOO-在生物分子硝化反应中的作用(嘌呤， 蛋白质和脂质)和受损的组织和血管结构/功能 在长期服用乙醇之后。2.调节NO和02- 产生(A)揭示氧化损伤对肝、肺和 血管系统，以及(B)减轻相关的组织和血管功能障碍 长期饮用酒精。3.利用靶向药理 减少慢性乙醇引起的生物分子硝化的干预措施 (嘌呤、蛋白质和脂肪)和随后的组织损伤和 血管结构/功能。这些观察结果将为 了解互动以了解的互动 超氧化物歧化与肝、肺、血管组织损伤 是由于长期服用乙醇造成的。获得机械洞察力 这些研究将指导药物干预措施的发展 限制活性物质的有害影响，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。

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.