FREE RADICALS IN ALCOHOLIC LIVER INJURY

肝硬变是一种严重的病理表现。 酗酒。虽然乙醇对多个方面的影响 肝功能已被广泛研究，特异性 酒精性肝病的病因尚不清楚。一 提出的机制是自由基导致的脂质过氧化 自由基介导的事件参与了疾病过程。在……里面 支持这一假设的初步实验已经 确定了以碳为中心的自由基在 急性和慢性给予乙醇的大鼠肝脏。这个 如果喂食大鼠，自由基产生的强度增加 增加脂肪含量以模拟 美国人的平均饮食习惯。建议的工作假设 研究认为，自由基可能与这一过程有关 从而导致慢性酒精引起的肝损伤 消费。 这项研究将确定乙醇 暴露会导致激进的形成。相关的抑制物 将利用酶系统来确定急性 肝脏损伤是由于过量的酒精或 乙醛；或其他反应性代谢物是否可能 在乙醇新陈代谢过程中产生。生理学 与乙醇相关的自由基的后果将是 通过评估肝脏的功能完整性进行调查 在加剧自由基形成的条件下。例如, 脂质过氧化指标、降低水平和总水平 谷胱甘肽、肝甘油三酯和代谢通量 将利用灌流的肝脏和分离的肝细胞来评估 乙醇染毒大鼠的肝功能。这项研究将 还描述了营养、生理和药理方面的特征 可能加重或拮抗肝损伤的干预措施 与酒精接触有关。此外，实验将是 被设计用来确定在 初步实验，以及其他可能是 在酒精喂养过程中诱导的。 这项研究的长期目标是利用EPR自旋陷阱 我们实验室开发的诱捕技术 体内自由基及探讨自由基在体内的作用 可能在酒精性肝病的病因学上有一定作用。如果这个机制 可以更好地了解疾病的过程，它可能是 有可能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方案。

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.