This grant is a continuation of our ongoing studies on mechanisms of chemically-induced hepatotoxicity. It is based on several novel observations made by our laboratory that have led us to conclude that nonparenchymal cells, in particular, macrophages, endothelial cells and fat storing cells, are critical cellular mediators of hepatotoxicity. Our laboratory was the first to report that hepatic macrophages accumulate in the liver and become functionally """"""""activated"""""""" following treatment of rats with hepatotoxicants. These activated mononuclear phagocytes release a cascade of inflammatory mediators including cytokines, reactive oxygen intermediates and nitric oxide which have the capacity to directly induce tissue injury and/or amplify the inflammatory response. Unexpectedly, during the course of our studies, we discovered that hepatic endothelial cells and fat storing cells also become functionally """"""""activated"""""""" to release inflammatory mediators following hepatotoxicant exposure. This was surprising since these cells are generally not considered to possess immunologic/inflammatory potential. We also discovered that there are marked differences in the extent of functional activation of nonparenchymal cells in the liver, as well as unique patterns of inflammatory mediator release following treatment of rats with acetaminophen or lipopolysaccharide. We hypothesize that localized accumulation and release of inflammatory and cytotoxic mediators by activated nonparenchymal cells in different regions of the liver contributes to the distinct hepatotoxic effects of these agents. In the present studies, in situ localization techniques will be used to characterize the kinetics and pattern of macrophage, endothelial cell and fat storing cell localization in the liver and release of inflammatory and cytotoxic mediators following treatment of rats with acetaminophen or lipopolysaccharide. The mechanisms by which these cells contribute to tissue injury will also be examined. Finally, we will evaluate the effects of modifying macrophage, endothelial cell and fat storing cell function and mediator release on hepatotoxicity. These studies will provide mechanistic insights into the role of nonparenchymal cells in hepatotoxicity and potential new approaches for pharmacologically abrogating hepatic injury associated with acetaminophen overdose or endotoxemia in humans.
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