MECHANISMS OF HEPATIC INJURY IN CHRONIC ALCOHOLICS

这项提案的总体目标是阐明 炎性中性粒细胞和激活的枯否细胞和内皮细胞 慢性酒精中毒的肝毒性诱导，以期 发展免疫治疗和生物技术方法 长期饮酒后组织损伤的治疗。这 这项提议是基于慢性酒精中毒的假设 调节黏附分子的表达和白细胞的侵袭 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趋化因子 暴露于乙醇后的细胞。因此，一系列广泛的 生物活性物质被释放，这可能有助于启动 易感人群的肝脏损伤的风险。它也是假设的 这样的事件可能会因内毒素而加剧。具体目标我会 研究黏附分子，即β2整合素的表达 中性粒细胞上的选择素和Kupffer上的对抗受体， 内皮细胞和肝细胞。这些分子对于 酒精后炎性中性粒细胞滞留到肝脏 侮辱。特殊目标2将检查氧衍生的形成 自由基、细胞溶解蛋白、促炎细胞因子和趋化因子 在肝脏中，它们被认为有助于诱导 慢性酒精中毒患者的组织损伤。根据特定的结果 目标1和目标2，具体目标3检验假设，通过中和 这些代谢物及其来源的有害影响(例如， 中性粒细胞和巨噬细胞)，肝损伤将减轻或 被禁止了。这将通过使用自由基清除剂来实现， 蛋白水解酶抑制剂、抗黏附分子的单抗和 脂质体包裹的二氯亚甲基二磷酸盐(特指 以库普弗细胞为靶标)。这个提议是独特的，也是新颖的，因为它 将使用现代免疫学和生物技术方法 慢性酒精性肝病的治疗。自由基的使用 清道夫、脂质体和单抗在免疫治疗中的应用 内毒素血症、癌症、缺血再灌注和免疫抑制 获得认可，也可应用于组织的治疗 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.