Ethanol effects on liver in self-administering primates

描述(申请人提供)：使用动物模型的大多数方案 为研究酒精性肝病的发生发展，利用 正在将乙醇作为饮食的一部分进行注射。这些型号提供了 我们目前掌握的大部分信息都是关于 与酗酒有关的肝脏损害的发展。到目前为止，有 没有自愿饮酒导致不可逆转的动物模型 肝脏损害；即超过脂肪肝阶段的损害。建议进行的研究 这个应用程序旨在确定非人类灵长类动物是否 自我给予乙醇将显示肝脏病理预测 酒精性肝炎和纤维化的发展。11只束猕猴 猴子将在一年内免费获得饮用水中的乙醇。 这些动物之前曾被训练自愿饮用乙醇，并 有些人每天的饮用量高达4g/kg，相当于到 一个人类。饮酒量较大的人平均血液酒精浓度为170 在先前的协议中为mg/dl。在拟议的研究中，轻度、中度和 酗酒者将包括在内，包括6名女性和5名男性。 将通过对血液样本的分析来寻找肝脏损伤的证据， 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。 将测量尿中异前列腺素的浓度以筛查 乙醇相关的氧化应激。每隔3天取一次肝穿活检样本 将通过光镜和电子显微镜检查肝脏的指标。 损害，如肝细胞气球、马洛里小体形成、炎症 和纤维化症。将进行免疫组织化学分析以检测 炎症、细胞凋亡和星状细胞激活的水平。目标 本研究的主要目的是：1)确定自给药束支原体 将在脂肪肝阶段后发展为肝脏病理和2)评估 用血、尿标本追踪酒精中毒患者病情发展的效果观察 动物模型中的肝病。

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.