The first rat model of alcoholic liver fibrosis has been developed by us during the past funding years. Our long-term goal is now aimed toward the understanding of cellular and molecular mechanisms involved in progression of alcoholic liver injury reproduced in this model. Three major findings have recently been obtained in this model. First, as a nutritional factor, the increased intake of polyunsaturated fat was shown to be key for induction of alcoholic liver fibrosis in our model of intragastric ethanol infusion. Secondly, the accentuated centrilobular hypoxia was indeed shown to be associated with induction of alcoholic centrilobular liver necrosis, and this pathophysiological event was attributable to the incomplete compensation of enhanced hepatic oxygen consumption by a limited increase in oxygen delivery , Lastly, in alcoholic liver fibrogenesis, hepatic lipocytes were activated to exhibit a 2-3 time higher basal rate of proliferation and a 50% greater basal rate of collagen formation. In addition, Kupffer cells were also induced to release mediators which has profound stimulatory effects on the activated lipocytes resulting in 2.5 times greater collagen formation with 14 times more active proliferative activity by these cells. To further extend our findings from previous and ongoing studies, we propose to investigate; 1) roles of the high fat diet and portal-systemic shuntting in the ethanol-induced centrilobular hypoxia; 2) cellular consequences of the centrilobular hypoxia; 3) identification of Kupffer cell-derived mediators responsible for stimulation of lipocytes; 4) cellular and molecular mechanisms of lipocyte and Kupffer cell activation; and 5) Kupffer cell-modulation of hepatocytes in alcoholic liver injury.
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