2-phenyl-4-4-5-5-tetramethylimidazoline-1-oxyl-3-oxide and Chemical-and-Drug-Induced-Liver-Injury

In wild-type BALB/c mice, i.p. administration of acetaminophen (APAP; 750 mg/kg) induced intrahepatic IFN-gamma mRNA expression and a marked increase in serum transaminase levels, leading to acute lethality of approximately 45%. Histopathological examination showed centrilobular hepatic necrosis with leukocyte infiltration and a large number of apoptotic hepatocytes 10 and 24 h after APAP challenge. mRNA expression of intercellular adhesion molecule 1, vascular cell adhesion molecule 1, interleukin (IL) 1alpha, IL-1beta, IL-6, tumor necrosis factor alpha, monocyte chemoattractant protein 1, macrophage inflammatory protein (MIP) 1alpha, MIP-2, KC, IP-10, Mig, Fas, and inducible nitric oxide synthase was enhanced in the liver of wild-type mice injected with APAP. To clarify the role of IFN-gamma in this process, IFN-gamma-deficient mice were treated in the same manner. All IFN-gamma-deficient mice survived with reduced serum transaminase elevation and attenuated hepatic necrosis, leukocyte infiltration, and hepatocyte apoptosis. The gene expression of all molecules was significantly attenuated in IFN-gamma-deficient mice. Administration of an anti-IFN-gamma neutralizing antibody even 2 or 8 h after APAP challenge to wild-type mice alleviated APAP-induced liver injury, and all mice survived. Thus, IFN-gamma is responsible for APAP-induced liver injury by mediating leukocyte infiltration, hepatocyte apoptosis, and NO production as well as cytokine and chemokine production. Moreover, immunoneutralization of IFN-gamma may be therapeutically effective for developing APAP-induced liver injury.

Topics: Acetaminophen; Acute Disease; Animals; Apoptosis; Cell Adhesion Molecules; Chemical and Drug Induced Liver Injury; Cyclic N-Oxides; Cytokines; Emigration and Immigration; Enzyme Inhibitors; Free Radical Scavengers; Imidazoles; Interferon-gamma; Leukocytes; Liver; Liver Diseases; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; RNA, Messenger; Survival Analysis