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 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.
Ogawa
M
M
First Department of Internal Medicine, Chiba University School of Medicine, Japan.
Mori
Y
Y
Ueda
S
S
Mori
T
T
Makino
Y
Y
Hori
J
J
Ohto
M
M
Wakashin
M
M
D000208:Acute Disease; D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000517:prevention & control*; D001550:Benzamidines; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000517:prevention & control*; D004731:Endotoxins / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors; D006146:Guanidines / Q000627:therapeutic use*; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000188:drug therapy; D007114:Immunization; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011506:Proteins / Q000276:immunology
D001550:Benzamidines; D004731:Endotoxins; D006146:Guanidines; D011480:Protease Inhibitors; D011506:Proteins; C032855:nafamostat