ROLE OF LIVER IN THE IMMUNODEFICIENCY OF ALCOHOLICS

本提案的总体目标是通过以下方式阐明机制： 酒精调节生物活性的几个方面， 中性粒细胞和单核吞噬细胞的表面特征，从而 导致酗酒者的免疫缺陷。 具体来说， 建议将调查受伤后的机制， 通过研究细胞相互作用， 在实质细胞和非实质细胞之间（Kupffer，内皮细胞& 中性粒细胞）。 在酒精中毒和内毒素血症时，这些细胞 类型可能相互作用，导致免疫反应受损， 引起肝脏组织损伤 这项提案还将调查 调节中性粒细胞、枯否细胞和内皮细胞功能，因为它们 与细胞损伤和炎症的发生、发展有关， 乙醇中毒伴或不伴内毒素血症。 的机制 白细胞-内皮细胞-巨噬细胞相互作用和 将检查体内和体外的相关细胞因子。 为了 实现这些目标，我将检查趋化因子的释放， 如C5 a、白三烯B4、白细胞介素1和8以及肿瘤坏死因子 伴有或不伴有内毒素血症。 吞噬细胞吞噬能力的体外研究 与上述趋化因子相互作用。 有关 通过这些研究， 在酒精中毒和内毒素血症期间进行研究。 后果 使用体外共培养的中性粒细胞或枯否细胞外渗 系统将用于补充先前的研究。 此外 产生超氧阴离子，蛋白水解酶如组织蛋白酶G和 将测定弹性蛋白酶。 这些物质的潜在破坏性， 将在共培养系统中研究内皮细胞和肝细胞。 硫代巴比妥酸反应测定脂质 将使用过氧化来评估组织或细胞损伤。 用于体外 将采用细胞毒性试验、51 Cr-释放和ASAT/ALAT试验。 上述实验模型将进一步使用 4-甲基吡唑（乙醇脱氢酶抑制剂）乙醛，α-1- 蛋白酶抑制剂，布洛芬（环氧合酶抑制剂），超氧化物 歧化酶和别嘌呤醇。 施行本 研究的目的是描述乙醇代谢物，氧- 衍生自由基、前列腺素和蛋白酶对组织损伤的影响， 免疫缺陷。 吞噬细胞调节的机制 将使用蛋白激酶C的调节剂研究其功能， 吞噬细胞中的NADPH氧化酶。

The overall objective of this proposal is to elucidate the mechanisms by which alcohol modulates several aspects of the biological activities and surface characteristics of neutrophils and mononuclear phagocytes, thereby contributing to the immunodeficiency of alcoholics. Specifically, this proposal will investigate the mechanisms responsible for injury after ethanol treatment or consumption by studying the cellular interactions between parenchymal and non-parenchymal cells (Kupffer, endothelial cells & neutrophils). During ethanol intoxication and endotoxemia, these cell types may interact to cause impairment of the immune response and to provoke tissue injury in the liver. This proposal will also investigate the modulation of neutrophil, Kupffer and endothelial cell function as they relate to the onset, development of cellular injury and inflammation during ethanol intoxication with or without endotoxemia. The mechanisms of leukocyte-endothelial cell-macrophage interaction and the release of relevant cytokines in vivo and in vitro will be examined. In order to achieve these goals, I will examine the release of chemotactic factors, such as C5a, leukotriene B4, interleukins 1 & 8, and tumor necrosis factor with or without endotoxemia. In vitro studies on the ability of phagocytes to interact with the above chemotaxins will be performed. In connection with these studies the modulation of receptors for selected ligands will be investigated during ethanol intoxication and endotoxemia. Consequences of neutrophil or Kupffer cell extravasation using an in vitro co-culture system will be used to complement the preceding studies. Furthermore the generation of superoxide anion, proteolytic enzymes such as cathepsin G and elastase will be determined. The destructive potential of these agents to endothelial cells and hepatocytes will be studied in a co-culture system. The thiobarbituric acid reaction for the determination of lipid peroxidation will be used to assess tissue or cell damage. For in vitro cytotoxicity assay, 51Cr-release and ASAT/ALAT assays will be employed. The above experimental models will be further manipulated with the use of 4-methypyrazole (inhibitor of alcohol dehydrogenase) acetaldehyde, alpha-1- protease inhibitor, ibuprofen (cyclooxygenase inhibitor), superoxide dismutase and allopurinol in vivo and in vitro. The purpose of these studies is to delineate the contribution of ethanol metabolites, oxygen- derived radicals, prostanoids and proteases on tissue injury and immunodeficiency. The mechanisms underlying the modulation of phagocyte function will be studied with the use of modulators of protein kinase C and NADPH oxidase in phagocytes.