FREE RADICALS IN ALCOHOLIC LIVER INJURY

肝硬化是一种严重的病理表现， 酗酒 虽然乙醇对各个方面的影响， 肝功能已被广泛研究，具体 酒精性肝病的病因尚不清楚。 一 提出的机制是脂质过氧化导致的自由 自由基介导的事件参与疾病过程。 在 为了支持这一假设，初步实验已经 建立了碳中心自由基产生于 急性和慢性给予乙醇的大鼠肝脏。 的 自由基产生强度增加，如果大鼠喂养 增加脂肪含量以模拟 美国的平均饮食 对拟议的工作假设 研究表明，自由基可能与过程有关， 导致慢性酒精引起的肝损伤 消费 这项研究将确定乙醇 暴露导致自由基形成。 相关抑制剂 酶系统将用于确定是否急性 肝损伤是由于高水平的乙醇或 乙醛;或是否其他反应性代谢物可能是 在乙醇代谢过程中产生。 生理 乙醇相关自由基的后果将是 通过评估肝脏的功能完整性进行研究 在强化自由基形成的条件下。 比如说， 脂质过氧化指标、还原型和 谷胱甘肽，肝甘油三酯和代谢通量率， 灌注的肝脏和分离的肝细胞将用于评估 暴露于乙醇的大鼠的肝功能。 这项研究将 还描述了营养、生理和药理学特征 可能增强或拮抗肝损伤的干预措施 与酒精接触有关。 此外，实验将 旨在确定检测到的自由基的身份， 初步的实验，以及其他可能的自由基 在乙醇进料期间诱导。 本研究的长期目标是利用EPR自旋捕获 我们实验室开发的技术 自由基在体内的作用，并探讨自由基， 酒精性肝病的病因可能有 如果机制 疾病的过程可以更好地理解，它可能是 可以减少或预防酒精中毒的肝脏并发症， 或者更好地为重病患者制定治疗计划。

Cirrhosis of the liver is a serious pathological manifestation of alcohol abuse. Although effects of ethanol on various aspects of hepatic function have been studied extensively, the specific causes of alcoholic liver disease are not understood. One proposed mechanism is that lipid peroxidation resulting from free radical-mediated events is involved in the disease process. In support of this hypothesis, preliminary experiments have established that carbon-centered free radicals are generated in livers of rats administered ethanol acutely and chronically. The intensity of radical generation was increased if the rats were fed diets in which the fat content was increased to simulate that of the average U.S. diet. The working hypothesis for the proposed studies is that the radical may be associated with the process which results in liver injury caused by chronic ethanol consumption. This research will determine mechanisms by which ethanol exposure leads to radical formation. Inhibitors of pertinent enzyme systems will be utilized to establish whether acute hepatic injury occurs as a result of high levels of ethanol or acetaldehyde; or whether other reactive metabolites may be generated during ethanol metabolism. The physiological consequences of the ethanol-associated radicals will be investigated by assessing the functional integrity of the liver under conditions which intensify radical formation. For example, indicators of lipid peroxidation, levels of reduced and total glutathione, hepatic triglycerides, and metabolic flux rates in perfused livers and isolated hepatocytes will be utilized to assess hepatic function in rats exposed to ethanol. This research will also characterize nutritional, physiological, and pharmacological interventions which may potentiate or antagonize hepatic damage related to ethanol exposure. In addition, experiments will be designed to establish the identity of the radical detected in preliminary experiments, as well as other radicals that may be induced during ethanol feeding. The long-term goal of this research is to utilize EPR spin-trapping techniques that have been developed in our laboratories to trap free radicals in vivo and investigate the roles that free radicals may have in etiology of alcoholic liver disease. If the mechanism of the disease process could be better understood, it may be possible to reduce or prevent hepatic complications of alcoholism, or to better plan therapy for seriously ill patients.