LIVER AND THE IMMUNODEFICIENCY OF ALCOHOLICS

描述：(改编自《调查员摘要》)本提案是一项 目前“一等奖”资助项目的延期(作为R01)， 题为“肝脏在酗酒者免疫缺陷中的作用”(R29 AA08846)。由这笔赠款支持的研究表明， 酒精对肝脏的影响是一个悖论。基于这些观察，总体上 这项建议的目的是研究急性或慢性疾病的机制 慢性酒精中毒对肝脏免疫功能的某些调节作用 有助于肝损伤和肝损伤发展的系统 免疫抑制。假设1：慢性酒精中毒导致 内毒素进入循环，进而刺激肝脏 巨噬细胞产生巨噬细胞炎症蛋白-2(MIP2)，一种有效的 刺激中性粒细胞趋化、释放超氧化物和肝脏毒性。 因此，黏附分子的表达增强了 白细胞和肝细胞，这可能导致增加迁移 肝脏中的炎性中性粒细胞，导致肝脏损伤。 具体目标1：确定慢性酒精中毒对 血清内毒素、体内外MIP2产生、黏附分子 外周血中中性粒细胞和肝细胞的表达与肝毒性 测定内毒素清除量。假设2：戒酒后， 急性酗酒加剧了内毒素休克的毒性效应。 具体目标2：确定酒精对内毒素血症的影响 停用肿瘤坏死因子和MIP2的产生，中性粒细胞的肝脏迁移，以及 肝脏非实质细胞自发产生超氧阴离子。 酒精戒断对脂多糖诱导的死亡率和肝损伤的影响 将会被研究。假设3：免疫抑制更常见 在慢性酗酒者中遇到，这可能部分是由于 调节抗原或配体引起的呼吸爆发。具体目标3： 研究长期饮酒对健康的影响 调理大肠杆菌诱导胞外超氧化物的产生 枯否细胞阴离子及细胞内过氧化氢和Fc受体的表达。 这些细胞的杀菌活性或缺乏杀菌活性将通过以下方式进行测试 以活的E.Coli为靶细胞。这个建议很独特，也很新颖 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(MIP2)对血管内皮细胞的诱导作用 与酒精相关的肝脏损伤。拟议的研究还包括 酒精对Fc受体表达调控作用的研究 库普弗细胞的呼吸爆发。将从以下位置生成的结果 这一竞争性续约预计将提供新的和令人兴奋的 可能对免疫治疗有重要应用的信息 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.