Ethanol effects on liver in self-administering primates

描述（由申请人提供）：大多数采用动物模型的方案 为了研究酒精性肝病的发展， 正在服用乙醇作为饮食的一部分。这些模型提供了 我们目前所掌握的关于有助于 与酒精滥用相关的肝损伤的发展。迄今为止， 没有动物模型自愿乙醇消费导致不可逆转的 肝损伤;即，脂肪肝的危害建议的研究 该应用程序旨在确定非人类灵长类动物是否 自我给予乙醇将证明肝脏病理学预测 酒精性肝炎和纤维化的发展。十一食蟹猴 猴子将在1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， 有些人每天摄入4克/公斤，相当于每天喝16杯， 一个人类酗酒者的平均血液酒精浓度为170 mg/dl，在之前的方案中。在拟议的研究中，轻度、中度和 将包括酗酒者，其中包括6名女性和5名男性。 肝损伤的证据将通过血液样本的分析来寻找， 将包括γ-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、球蛋白和其他血液成分。 将测量异前列腺素的尿液浓度，以筛选 乙醇相关的氧化应激肝穿刺活检样本，每3 个月，将通过光学和电子显微镜检查肝脏指数 损伤，如肝细胞气球样变、马洛里体形成、炎症 和纤维化。将进行免疫组织化学分析， 炎症、凋亡和星状细胞活化水平。目标 本研究的目的是：1）确定是否自我管理M。fascicularis 将在脂肪肝阶段之后发展肝脏病理学，以及2）评估 使用血液和尿液样本追踪酒精中毒发展的有效性 肝病动物模型

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.