MECHANISMS OF HEPATIC INJURY IN CHRONIC ALCOHOLICS

本提案的总体目标是阐明 炎症中性粒细胞和激活的枯否细胞和内皮细胞对 在慢性酒精中毒者中诱导肝毒性， 开发免疫学和生物技术方法， 治疗长期饮酒后的组织损伤。这 这项建议是基于慢性酒精中毒的假设， 调节粘附分子的表达和白细胞浸润 进入肝脏这种事件也可以通过释放 肝细胞、枯否细胞和内皮细胞释放的趋化因子 暴露于乙醇后的细胞。因此，广泛的 生物活性物质的释放可能有助于启动 易感个体的肝损伤。也有人假设 内毒素可能会加剧这些事件。具体目标我会 研究粘附分子的表达，即，β 2-整联蛋白 中性粒细胞上的选择素和枯否细胞上的反受体， 内皮细胞和肝细胞。这些分子对于 酒精后炎性中性粒细胞进入肝脏 侮辱。具体目标2将检查氧衍生的 自由基、溶细胞蛋白酶、促炎细胞因子和趋化因子 在肝脏中，这被认为有助于诱导 慢性酗酒者的组织损伤根据具体的结果， 目标1和2，具体目标3审查了以下假设： 这些代谢物的有害作用及其来源（例如，G. 中性粒细胞和巨噬细胞），肝损伤将被减弱，或 压抑这将通过使用自由基清除剂来实现， 蛋白酶抑制剂，抗粘附分子的单克隆抗体， 脂质体包封的二氯亚甲基二膦酸酯（其具体地 靶向枯否细胞）。这一建议是独特和新颖的，因为它 将使用现代免疫学和生物技术方法， 治疗慢性酒精中毒者的肝脏疾病。自由基的使用 清除剂，脂质体和单克隆抗体在免疫治疗 内毒素血症、癌症、缺血-再灌注和免疫抑制， 并且还可以应用于组织的治疗 慢性酒精中毒时肝脏和其他器官的损伤。

The overall objective of this proposal is to elucidate the role of inflammatory neutrophils and activated Kupffer and endothelial cells on the induction of hepatotoxicity in chronic alcoholics, with a view to developing immunotherapeutic and biotechnological methods for the treatment of tissue injury after prolonged alcohol consumption. This proposal is based on the hypothesis that chronic alcohol intoxication regulates the expression of adhesion molecules and leukocyte infiltration into the liver. Such event may also be mediated by the release of chemotractant factors released by hepatocytes, Kupffer and endothelial cells after exposure to ethanol. As a consequence, a wide spectrum of bioactive substances are released that may contribute to the initiation of hepatic injury in susceptible individuals. It is also hypothesized that such events may be exacerbated by endotoxin. Specific aim I will investigate the expression of adhesion molecules, i.e., Beta2-integrins and selectins on neutrophils and their counterreceptors on Kupffer, endothelial cells and hepatocytes. These molecules are important for the sequestration of inflammatory neutrophils into the liver after an alcohol insult. Specific aim 2 will examine the formation of oxygen-derived radicals, cytolytic proteases, proinflammatory cytokines and chemokines in the liver, which are considered to contribute to the induction of tissue injury in chronic alcoholics. Based on the results of specific aims 1 & 2, specific aim 3 examines the hypothesis that by neutralizing the deleterious effects of these metabolites and their sources (e. g. neutrophils and macrophages), hepatic injury will be attenuated or inhibited. This will be achieved by using free radical scavengers, protease inhibitors, monoclonal antibodies against adhesion molecules and liposome encapsulated dichloromethylene diphosphonate (which specifically targets Kupffer cells). This proposal is unique and novel, because it will use modern immunological and biotechnological approaches for the treatment of liver disease in chronic alcoholics. The use of free radical scavengers, liposomes and monoclonal antibodies in the immunotherapy of endotoxemia, cancer, ischemia-reperfusion and immunosuppression is gaining acceptance, and may also be applied to the treatment of tissue injury in the liver and other organs during chronic alcohol intoxication.