LIVER AND THE IMMUNODEFICIENCY OF ALCOHOLICS

描述：（改编自研究者摘要）本提案是一项 目前“FIRST奖”资助项目的扩展（作为R 01）， 题为“肝脏在酗酒者免疫缺陷中的作用（R29 AA08846）。 这项资助支持的研究表明， 酒精对肝脏的影响是个悖论 根据这些观察， 这项建议的目的是审查机制， 慢性酒精中毒调节肝脏免疫的某些方面， 系统，有助于肝损伤的发展， 免疫抑制 假设1：慢性酒精中毒 循环中的内毒素流入，这反过来刺激肝脏 巨噬细胞产生巨噬细胞炎性蛋白-2（MIP 2），一种有效的 刺激PMN趋化性、超氧化物释放和肝毒性。 因此，有增强的粘附分子的表达， 白细胞和肝细胞，这可能导致增加的迁移， 肝脏中的炎性PMN（中性粒细胞），导致肝损伤。 具体目标1：确定慢性酒精中毒对 血清内毒素，体内外MIP 2生成，粘附分子 外周血中性粒细胞和肝细胞的表达，以及肝毒性， 测定LPS清除率。 假设2：酒精戒断， 急性酗酒会加重内毒素休克的毒性作用。 具体目标2：确定饮酒期间内毒素血症的影响 停药对TNF和MIP 2产生、PMN的肝迁移以及 肝非实质细胞自发产生超氧阴离子。 酒精戒断对脂多糖所致肝损伤及死亡率的影响 将被研究。 假设3：免疫抑制更频繁 在慢性酗酒者中遇到，这可能部分是由于 调节抗原或配体诱导的呼吸爆发。 具体目标3： 研究长期饮酒对 调理剂诱导的大肠杆菌胞外超氧化物的产生 阴离子和细胞内H2 O2和Fc受体表达的Kupffer细胞。 这些细胞的杀微生物活性或缺乏杀微生物活性，将通过 利用活的E.大肠杆菌作为靶细胞。 这一提议独特而新颖 因为它将阐明一种新发现的趋化因子的作用， 巨噬细胞炎性蛋白-2（MIP 2）对诱导 酒精性肝损伤 拟议的研究还包括 酒精介导的Fc受体表达调控作用的研究 和库普弗细胞的呼吸爆发。 将产生的结果 这一竞争性的更新预计将提供新的和令人兴奋的 可能对免疫治疗具有重要应用的信息， 肝脏因创伤或感染而进一步受损的酗酒者。

DESCRIPTION: (Adapted from the Investigator's Abstract) This proposal is an extension (as an R01) of the currently "FIRST award"-funded project, entitled "The role of the liver in the immunodeficiency of alcoholics (R29 AA08846). Studies supported by this grant demonstrated that the effect of alcohol on the liver is a paradox. Based on these observations, the overall objective of this proposal is to examine the mechanisms by which acute or chronic alcohol intoxication regulates some aspects of the hepatic immune system that contribute to the development of hepatic injury and immunosuppression. Hypothesis 1: Chronic alcohol intoxication induces endotoxin influx in the circulation which in turn stimulates hepatic macrophages to produce macrophage inflammatory protein-2(MIP2), a potent stimulus for PMN chemotaxis, superoxide release and hepatotoxicity. Consequently, there is enhanced expression of adhesion molecules on leukocytes and hepatic cells, which can lead to increased migration of inflammatory PMNs (neutrophils) in the liver, resulting in hepatic injury. Specific aim 1: To determine the effect of chronic alcohol intoxication on serum endotoxin, MIP2 production in vivo and in vitro, adhesion molecule expression on peripheral PMNs and hepatic cells, and hepatotoxicity and to determine LPS clearance. Hypothesis 2: Alcohol withdrawal, following an acute alcohol binge exacerbates the toxic effects of endotoxic shock. Specific aim 2: To determine the effect of endotoxemia during alcohol withdrawal on TNF and MIP2 production, hepatic migration of PMNs, and spontaneous superoxide anion production by hepatic non-parenchymal cells. The effect of alcohol withdrawal on LPS-induced mortality and hepatic injury will be studied. Hypothesis 3: Immunosuppression is more frequently encountered among chronic alcoholics, which may be partially due to the down regulation of antigen or ligand-induced respiratory burst. Specific aim 3: To study the effect of prolonged consumption of alcohol on opsonized-Escherichia coli-induced production of extracellular superoxide anion and intracellular H2O2 and Fc receptor expression on Kupffer cells. The microbicidal activity of these cells or, lack thereof, will be tested by using viable E. Coli as target cells. This proposal is unique and novel because it will elucidate the role of a newly discovered chemokine, macrophage inflammatory protein-2 (MIP2) on the induction of alcohol-associated liver injury. The proposed research also includes studies on the role of alcohol-mediated regulation of Fc receptor expression and respiratory burst in Kupffer cells. Results that will be generated from this competitive renewal are expected to provide new and exciting information that may have an important application for the immunotherapy of alcoholics whose livers are further compromised by trauma or infection.