Ethyl pyruvate reduces liver injury in a murine model of extrahepatic cholestasis

Ethyl pyruvate has been shown to ameliorate liver injury and decrease expression of several proinflammatory cytokines when used to treat mice with hemorrhagic shock or alcoholic hepatitis. Herein we sought to determine whether delayed treatment with ethyl pyruvate dissolved in a Ringer's-type balanced salt solution-Ringer's ethyl pyruvate solution (REPS)-would be beneficial in a murine model of common bile duct ligation (CBDL)-induced liver injury. Male C57BL/6 mice were subjected to a sham (n = 6) procedure or CBDL (n = 27). Twenty-four hours after operation, mice subjected to CBDL were randomized to receive treatment with either REPS (40 mg/kg of ethyl pyruvate per dose) or Ringer's lactate solution (RLS) every 8 h over a 72 h period. Compared with sham-treated controls, CBDL in RLS-treated mice was associated with histological evidence of hepatocellular necrosis as well as significant increases in the plasma concentrations of alanine aminotransferase and total bilirubin. Relative to sham-treated controls, CBDL in RLS-treated mice also was associated with increased hepatic lipid peroxidation and increased hepatic expression of transcripts for TNF, IL-6, and iNOS. All of these changes were significantly attenuated by delayed treatment with REPS after CBDL. In the RLS-treated group, CBDL was associated with increased NF-kappaB DNA binding in nuclear extracts prepared from liver tissue. Treatment with REPS increased NF-kappaB DNA binding still further. CBDL was associated with increased hepatocellular apoptosis in both the RLS- and REPS-treated groups. These data support the view that ethyl pyruvate ameliorates hepatic inflammation, lipid peroxidation, and necrosis in mice subjected to CBDL. Ethyl pyruvate warrants further evaluation as an adjunctive treatment to ameliorate liver injury from extrahepatic biliary obstruction.