Experimental
autoimmune hepatitis was induced in C57BL/6 mice by immunization with syngeneic liver
protein and adjuvant.
Hepatitis was characterized by marked cellular infiltrates, but hepatic
necrosis was mild to moderate. A small dose of
endotoxin (25 micrograms/mouse) produced lethal
hepatitis with elevation of serum
transaminase levels in these mice. The
endotoxin-induced reactions were completely inhibited by i.p. administration of
FUT-175 (5 mg/kg), a synthetic
protease inhibitor, 1 h before the
endotoxin injection. In vitro experiments showed that two-thirds of the inflammatory infiltrates were monocyte/macrophages. Cytotoxicity against syngeneic hepatocytes was significantly increased by the addition of
endotoxin (25 micrograms/ml), but the same dose of
endotoxin alone had no effect on the viability of hepatocytes. The
endotoxin-induced increase in cytotoxicity was prominent in the glass-dish adherent (monocyte/macrophage enriched) fraction and was also demonstrated after 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
endotoxin are mediated, at least in part, by monocytes or macrophages infiltrating the liver following immunization of liver
proteins. Our results also suggest that
FUT-175 has protective effects against
endotoxin-induced hepatotoxic reactions.