FREE RADICALS IN ALCOHOLIC LIVER INJURY

描述(摘自申请者摘要)：酒精性肝硬变 是长期酗酒的严重后果。虽然酒精 导致正常肝功能的许多变化，具体原因是 酒精性肝病目前尚不清楚。一种拟议的机制是 急性和慢性饮酒后产生的自由基可能是 对引发肝脏损伤负有责任。这一假设将通过以下方式检验 利用自旋捕获法和EPR光谱进行检测和鉴定 暴露在酒精中的大鼠体内形成的自由基。在第一个 具体目的：Wistar大鼠连续灌胃酒精 输液，以及含有以下三种类型之一的液体饮食 膳食脂肪。当鱼油是脂肪的来源时，大鼠会发展成严重的肝脏。 在四周内坏死，而更中度的损伤观察到当 饮食中含有玉米油。如果饱和脂肪和酒精一起喂养，脂肪 肝脏会发育，但不会出现更严重的肝损伤。喂食的大鼠 用葡萄糖代替酒精的流质饮食不会发育成肝脏 疾病。在喂食这些食物的大鼠的肝脏中检测到的自由基 治疗方案的特征将与组织学评估进行比较。 确定自由基形成与肝脏关系的组织 受伤。在第二个具体目标中，抑制剂和抗氧化剂将 用于探讨1-羟乙基自由基形成的调控机制 和肝脏中的脂类自由基。这些实验将在 给未处理的大鼠和喂食的大鼠急性酒精灌胃 液体酒精或对照饮食。将进行更多的实验 测定酒精通过游离态代谢的部分 自由基途径，并评估乙醛可能在 引发自由基反应。最后，水杨酸盐和D-苯丙氨酸 将其应用于大鼠以测试羟基自由基的形成是否 急性或慢性饮酒后增加。来自这些网站的数据 研究将有助于确定自由基在酒精性肝脏中的作用 可能会造成伤害，并可能导致制定预防措施。

DESCRIPTION (from Applicant's Abstract): Alcoholic cirrhosis of the liver is a serious consequence of long-term alcohol abuse. Although alcohol causes many changes in normal liver function, the specific causes of alcoholic liver disease are not understood. One proposed mechanism is that free radicals generated after acute and chronic alcohol consumption may be responsible for initiating liver injury. This hypothesis will be tested by using the spin trapping method and EPR spectroscopy to detect and identify radicals formed in rats which have been exposed to alcohol. In the first specific aim, Wistar rats will be fed alcohol by continuous intragastric infusion, along with liquid diets which contain one of three types of dietary fat. When fish oil is the source of fat, rats develop severe liver necrosis within four weeks, while more moderate injury is observed when the diet contains corn oil. If saturated fat is fed along with alcohol, fatty liver develops, but more serious forms of liver injury are absent. Rats fed the liquid diets with dextrose in place of alcohol do not develop liver disease. Radicals which are detected in livers from rats fed these dietary regimens will be characterized and compared with histological evaluation of the tissue to determine the relationship between radical formation and liver injury. In the second specific aim, inhibitors and antioxidants will be used to probe mechanisms which regulate formation of 1hydroxyethyl radicals and lipid radicals in the liver. These experiments will be conducted vhth acute alcohol administration to untreated rats, as well as to rats fed liquid alcohol or control diets. Additional experiments will be performed to determine the fraction of alcohol which is metabolized through a free radical pathway, and to assess the role that acetaldehyde may have in initiating free radical reactions. Finally, salicylate and D-phenylalanine will be administered to rats to test whether hydroxyl radical formation is increased after acute or chronic alcohol administration. Data from these studies will help to define roles that radicals have in alcoholic-liver injury, and may lead to development of preventative measures.