Protective effects and possible mechanisms of hepatic fibrosis against APAP-induced lethal injury

Abstract

To investigate the protective effects of hepatic fibrosis against a lethal dose of acetaminophen (APAP) and its underlying mechanisms using a carbon tetrachloride (CCl4)-induced mouse model of fibrosis. The experimental model of hepatic fibrosis was established by intraperitoneal injection of CC14 (in mineral oil), twice a week for 6 weeks; mice given a 6-week course of mineral oil injections served as normal controls. At the end of fibrosis induction, the expmimental (Fib group) and control (Norm group) mice were challenged with APAP (1 g/kg). Sera and liver tissues were harvested for analyses.To assess tolerance of the normal and fibrotic mice to the lethal dose of APAP, the survival rate,serum alanine aminotransferase (sALT) levels and hepatic histopathological changes were compared before and after the acute APAP challenge.HMGB 1 expression was analyzed by immunohistochemistry.One-way ANOVA test and Newman-Keuls test were used in statistical analysis. The fibrotic liver was tolerant to the lethal dose of APAP,as evidenced by:(1) significantly higher survival rate in the Fib ± APAP group (80% vs. Norm+APAP group: 0%); (2) markedly lower sALT levels in the Fib+APAP group (6 437 ± 1 913 U/L vs. 12 456 ± 3 441 U/L), P=0.022; (3) remarkably well-preserved liver architecture in the Fib+APAP group.Immunohistochemical analysis showed high HMGB1 expression and cytoplasmic translocation in the Norm+APAP group,which was absent in the Fib+APAP group. CCl4-induced liver fibrosis protects mice against lethal dose of APAP, Possibly by a mechanism involving inhibition of the cytoplasmic translocation of HMGB1.