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: 6460463
• 负责人: CAROL C CUNNINGHAM
• 金额: $ 14.41万
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6460463
• 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）：大多数采用动物模型的协议 用于研究酒精性肝病的发展，利用了大鼠 作为饮食的一部分，正在用乙醇给药。这些模型提供了 我们目前对有助于的机制的许多信息 与酒精滥用有关的肝脏损害的发展。迄今为止有 没有动物模型，自愿消耗导致不可逆的动物模型 肝损伤；即，经过脂肪肝阶段的损坏。提出的研究 该应用程序旨在确定非人类灵长类动物是否 自我管理乙醇将证明肝病病理学预测 酒精性肝炎和纤维化的发展。 11个杏仁麦筋膜 猴子将在饮用水中免费获得乙醇1年。 这些动物以前已经接受过自愿喝乙醇的训练， 有些消耗多达4g/kg/天，相当于每天16杯酒 人类。较重的饮酒者平均血乙醇浓度为170 先前协议中的mg/dl。在拟议的研究中，光线，中度和 将包括大量饮酒者，其中包括6名女性和5名男性。 肝脏损害的证据将通过对血液样本的分析来寻求 将包括测量Y-谷氨基转移酶，天冬氨酸和丙氨酸 转氨酶，胆红素，白蛋白，球蛋白和其他血液成分。 将测量异丙烷的尿液浓度以筛选 与乙醇相关的氧化应激。肝针活检样品，每3次服用 月份将通过光和电子显微镜检查肝脏指标 损坏，例如肝细胞气球，马洛里的身体形成，炎症 和纤维化。将实施LMMUNO组织化学分析以测量 炎症，凋亡和星状细胞活化的水平。目标 这项研究的是1）确定自我管理的fasticularis是否 将在脂肪肝阶段发展出肝脏病理，2）评估 使用血液和尿液样品遵循酒精的发展的功效 动物模型中的肝病。