PROTECTIVE EFFECTS OF FUT-175 ON ACUTE MASSIVE HEPATIC-NECROSIS INDUCED IN MICE FOLLOWING ENDOTOXIN INJECTION AND IMMUNIZATION WITH LIVER PROTEINS

Experimental autoimmune hepatitis was induced in C57BL/6 mice by immun ization with syngeneic liver protein and adjuvant. Hepatitis was chara cterized by marked cellular infiltrates, but hepatic necrosis was mild to moderate. A small dose of endotoxin (25 mu g/mouse) produced letha l hepatitis with elevation of serum transaminase levels in these mice. The endotoxin-induced reactions were completely inhibited by i.p. adm inistration of FUT-175 (5 mg/kg), a synthetic protease inhibitor, 1 h before the endotoxin injection. In vitro experiments showed that two-t hirds of the inflammatory infiltrates were monocyte/macrophages. Cytot oxicity against syngeneic hepatocytes was significantly increased by t he addition of endotoxin (25 mu g/ml), but the same dose of endotoxin alone had no effect on the viability of hepatocytes. The endotoxin-ind uced increase in cytotoxicity was prominent in the glass-dish adherent (monocyte/macrophage enriched) fraction and was also demonstrated aft er depletion of T-cells. However, elevated cytotoxicity did not occur when FUT-175 (>1 x 10(-7) M) was present throughout the assay period. These results seem to indicate that the hepatotoxic effects of endotox in are mediated, at least in part, by monocytes or macrophages infiltr ating the liver following immunization of liver proteins. Our results also suggest that FUT-175 has protective effects against endotoxin-ind uced hepatotoxic reactions.