Ethanol effects on liver in self-administering primates

乙醇对自我给药灵长类动物肝脏的影响

• 批准号: 6731958
• 负责人: CAROL C CUNNINGHAM
• 金额: $ 14.4万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6731958
• 关键词: Macaca fascicularis; alcoholic beverage consumption; alcoholic hepatitis; alcoholism /alcohol abuse; biological models; biopsy; blood tests; diagnosis design /evaluation; electron microscopy; ethanol; fibrosis; gender difference; immunocytochemistry; liver; liver disorder diagnosis; liver function; longitudinal animal study; model design /development; morphology; oxidative stress; pathologic process; self medication; urinalysis

DESCRIPTION (provided by applicant): Most protocols that employ animal models for studying the development of alcoholic liver disease utilize the rat that is being administered ethanol as part of the diet. These models have provided much of the information we presently have on the mechanisms that contribute to development of liver damage associated with alcohol abuse. To date there are no animal models where voluntary ethanol consumption has led to irreversible liver damage; i.e., damage past the fatty liver stage. The studies proposed in this application are designed to determine if non-human primates that are self-administering ethanol will demonstrate liver pathology predictive of the development of alcoholic hepatitis and fibrosis. Eleven Macaca fascicularis monkeys will be given free access to ethanol in drinking water for 1 year. These animals have been previously trained to drink ethanol voluntarily and some have consumed up to 4g/kg/day, which is equivalent to 16 drinks a day by a human. The heavier drinkers averaged blood ethanol concentrations of 170 mg/dl in a previous protocol. In the proposed studies, light, moderate and heavy drinkers will be included, which are comprised of 6 females and 5 males. Evidence for liver damage will be sought by analyses of blood samples, which will include measurements of y-glutamyltransferase, aspartate and alanine transaminases, bilirubin, albumin, globulin and other blood components. Urinary concentrations of isoprostanes will be measured to screen for ethanol-related oxidative stress. Liver needle biopsy samples, taken every 3 months, will be examined by light and electron microscopy for indices of liver damage, such as hepatocyte ballooning, Mallory body formation, inflammation and fibrosis. lmmunohistochemical analyses will be implemented to measure levels of inflammation, apoptosis and stellate cell activation. The objectives of this study are 1) to determine if the self-administering M. fascicularis will develop liver pathology past the fatty liver stage and 2) to evaluate the efficacy of using blood and urine samples to follow development of alcoholic liver disease in an animal model.

描述（由申请人提供）：大多数方案均采用动物模型 为了研究酒精性肝病的发展，利用了以下大鼠： 正在将乙醇作为饮食的一部分。这些模型提供了 我们目前掌握的许多有关机制的信息有助于 与酗酒相关的肝损伤的发展。迄今为止有 没有动物模型表明自愿消费乙醇会导致不可逆转的 肝损伤；即，损害已经过了脂肪肝阶段。中提出的研究 该应用程序旨在确定非人类灵长类动物是否 自我施用乙醇将证明肝脏病理学可预测 酒精性肝炎和纤维化的发展。食蟹猴 11只 猴子将在一年内免费获得饮用水中的乙醇。 这些动物之前已经接受过自愿饮用乙醇的训练 有些人每天的摄入量高达 4 克/公斤，相当于每天 16 杯饮料 一个人。酗酒者的平均血液乙醇浓度为 170 先前方案中的 mg/dl。在拟议的研究中，轻度、中度和 其中包括重度饮酒者，其中包括 6 名女性和 5 名男性。 将通过分析血液样本来寻找肝损伤的证据， 将包括 y-谷氨酰转移酶、天冬氨酸和丙氨酸的测量 转氨酶、胆红素、白蛋白、球蛋白等血液成分。 将测量异前列腺素的尿浓度以筛选 乙醇相关的氧化应激。肝穿刺活检样本，每 3 次采集一次 几个月，将通过光学和电子显微镜检查肝脏指标 损伤，例如肝细胞膨胀、马洛里小体形成、炎症 和纤维化。将进行免疫组织化学分析来测量 炎症、细胞凋亡和星状细胞激活的水平。目标 本研究的目的是 1) 确定自我给药的束状分枝杆菌是否 将在脂肪肝阶段之后发展出肝脏病理学，并且 2) 评估 使用血液和尿液样本追踪酒精发展的功效 动物模型中的肝病。