Effect of Alpha-Tocopherol on the Expression of Hepatic Vascular Stress Genes in Response to Sepsis

Abstract

Sepsis is the leading cause of death in critically ill surgical patients. Septic hepatic dysfunction, an important determinant of outcome, although poorly understood, includes inappropriate expression of vasoregulatory genes. In this study the effect of alpha-tocopherol was determined on the expression of hepatic vascular stress genes in response to sepsis. Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). Rats received either vehicle or alpha-tocopherol (AT, 15 mg/kg), intraperitoneally injected for 3 d prior to CLP procedure. Serum aminotransferase activities and hepatic lipid peroxides levels markedly increased 24 h after CLP, and this rise was attenuated by AT treatment. The hepatic concentrations of reduced glutathione decreased in CLP animals, which was inhibited by AT. CLP significantly increased mRNA levels of endothelin (ET)-1 and ETB receptor in livers, which was not prevented by AT treatment. There were no significant changes in ETA mRNA expression among any of the experimental groups. There were significant increases in the mRNA expression of inducible nitric oxide synthase and heme oxygenase-1 in livers of CLP animals, and this was prevented by AT treatment. The expression of tumor necrosis factor-α and cyclooxygenase-2 mRNA increased 4.9-fold and 4.4-fold, respectively, in livers of CLP animals. This increase was attenuated by AT treatment. Our data suggest that sepsis induces an imbalance in hepatic vasoregulatory gene expression and that AT ameliorates altered expression of vasodilators through its free radical scavenging activity.