ETHANOL AND HOST DEFENSE RELATED HEPATIC FUNCTION

乙醇是一种有效的免疫抑制剂， 患者是免疫功能低下的宿主。 酒精会使人易感 细菌和病毒感染，并增加发病率和死亡率。 在肝脏内，枯否细胞（常驻巨噬细胞）和 内皮细胞在监视 细菌或细菌产物肝脏也是主要的位置 乙醇的代谢。 因此，长期目标是 目前的建议是阐明机制的职能和 急性和慢性酒精中毒引起的代谢改变 和LPS或这些生物反应调节剂的组合， 枯否细胞和肝内皮细胞，以及在隔离 中性粒细胞 三个假设将被考虑：（1）乙醇改变 LPS、细胞因子或LPS诱导的摄取变化， 细胞中肝非实质细胞对葡萄糖的磷酸化 （2）乙醇中毒抑制LPS-、精氨酸-或 葡萄糖诱导的葡萄糖表达和合成增加 转运蛋白和己糖激酶和葡萄糖-6-P-脱氢酶; 乙醇对葡萄糖代谢的抑制作用 免疫应答导致免疫功能受损， 抗氧化性肝细胞损伤的保护机制。 假设#1将通过旨在确定 乙醇对内毒素（LPS）、葡萄糖、葡萄糖诱导的葡萄糖的影响 体内和体外摄取以及胰岛素和儿茶酚胺结合。 假设2的具体目标将决定乙醇和LPS或 细胞因子调节细胞的mRNA表达和蛋白质合成速率， 戊糖中葡萄糖进入和随后代谢的关键酶 周期 假设#3的具体目标集中在确定各种 肝非实质细胞的免疫功能依赖于 葡萄糖被这些细胞催化。 非特异性免疫改变 库普弗细胞和内皮细胞的功能，并在可能的情况下隔离 通过测定TNF、IL-1、IL-6的产生， 超氧阴离子和一氧化氮生成，吞噬作用，杀菌作用 活性和透明质酸摄取。 各种类型的葡萄糖代谢 将测量肝细胞类型，并测试乙醇 LPS修饰了这一重要的抗氧化机制。 这些研究将 提供了关于调节葡萄糖的基本机制的新信息 非实质细胞的利用和相关免疫功能，以及如何 两种有效的免疫调节剂乙醇和LPS相互作用， 这一途径和控制是宿主防御的一个重要方面。

Ethanol is a potent immunosuppressive agent and the alcohol-consuming patient is an immunocompromised host. Alcohol predisposes individuals to bacterial and viral infections, and increases morbidity and mortality. Within the liver, the Kupffer cells (resident macrophages) and endothelial cells plays an essential role in surveillance against bacteria or bacterial products The liver is also the primary location for the metabolism of ethanol. Therefore, the long-term goal of the present proposal is to elucidate the mechanisms for the functional and metabolic alterations produced by acute and chronic alcohol intoxication and LPS or the combination of these biological response modifiers in Kupffer and hepatic endothelial cells, as well as in sequestered neutrophils. Three hypotheses will be considered: (1) Ethanol alters LPS-, cytokine- or hormone-induced changes in the uptake and phosphorylation of glucose by hepatic nonparenchymal cells in a cell specific manner; (2)Ethanol intoxication inhibit LPS-,cytokine-or hormone-induced increased expression and synthesis of glucose transporters and hexokinase and glucose-6-P-dehydrogenase in these cells; and (3) The inhibitory effects of ethanol on the glucose metabolic response lead to impairments of immune-competent functions and hamper the protective mechanisms against oxidative hepatocellular injury. Hypothesis #1 will be addressed by specific aims directed at determining the effect of ethanol on the LPS, cytokine-or hormone-induced glucose uptake in vivo and in vitro, and insulin and catecholamine binding. Specific aims for hypothesis #2 will determine how ethanol and LPS or cytokines modulate the mRNA expression and protein synthesis rate of the key enzymes of glucose entry and subsequent metabolism in the pentose cycle. The specific aims for hypothesis #3 focus on determining various immune-competent functions of hepatic nonparenchymal cells dependent on glucose catabolism by these cells. Alteration in nonspecific immune functions of Kupffer and endothelial cells, and when possible sequestered neutrophils, will be assessed by determining TNF, IL-1, IL-6 production, superoxide anion and nitric oxide generation, phagocytosis, bactericidal activity and hyaluronic acid uptake. Glutathione metabolism in various hepatic cells types will be measured and it will be tested how ethanol and LPS modify this important anti-oxidant mechanism. These studies will provide novel information on the basic mechanisms regulating glucose utilization and related immune functions in nonparenchymal cells, and how two potent immunomodulatory agents, ethanol and LPS, interact to modulate this pathway and control an important aspect of host defense.