SINUSOIDAL LINING CELLS AND HEPATOTOXICITY

Treatment of experimental animals with toxic doses of acetaminophen, c arbon tetrachloride, phenobarbital, galactosamine, or endotoxin result s in an accumulation of macrophages in the liver. These mononuclear ph agocytes, as well as hepatic endothelial cells and stellate cells, are activated to release increased amounts of proinflammatory and cytotox ic mediators including hydrogen peroxide, superoxide anion, nitric oxi de, bioactive lipids, interleukin 1, platelet activating factor, and t umor necrosis factor a. Each of these mediators has the capacity to in duce 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 augment s toxicant-induced liver damage. These data provide direct support for a role of macrophages and inflammatory mediators in hepatotoxicity.