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.
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