Treatment of experimental animals with toxic doses of acetaminophen, carbon tetrachloride, phenobarbital, galactosamine, or endotoxin results in an accumulation of macrophages in the liver. These mononuclear phagocytes, as well as hepatic endothelial cells and stellate cells, are activated to release increased amounts of proinflammatory and cytotoxic mediators including hydrogen peroxide, superoxide anion, nitric oxide, bioactive lipids, interleukin 1, platelet activating factor, and tumor necrosis factor α. Each of these mediators has the capacity to induce tissue injury directly and/or augment the inflammatory response. When animals are treated with agents that block macrophage functioning and/or mediator release, xenobiotic-induced hepatotoxicity is reduced. In contrast, treatment of animals with macrophage activators augments toxicant-induced liver damage. These data provide direct support for a role of macrophages and inflammatory mediators in hepatotoxicity.
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