Delivery of I kappa B superrepressor gene with adenovirus reduces early alcohol-induced liver injury in rats

Chronic alcohol administration increases gut-derived endotoxin in the porta l blood, which activates Kupffer cells through nuclear factor kappaB (NF-ka ppaB) to produce toxic mediators such as proinflammatory cytokines, leading to liver injury. Therefore, a long-term intragastric ethanol feeding proto col was used here to test the hypothesis that NF-kappaB inhibition would pr event early alcohol-induced liver injury. Adenoviral vectors encoding eithe r the transgene for I kappaB superrepressor (AdI kappaB-SR) or the bacteria l beta -galactosidase reporter gene (AdlacZ) were administered intravenousl y to Wistar rats. Animals were fed a high-fat liquid diet with either ethan ol or isocaloric maltose-dextrin (control) for 3 weeks. There was no signif icant difference in mean urine alcohol concentrations between the groups fe d ethanol. I kappaB-SR expression was increased for up to 2 weeks after inj ection, but was undetectable at 3 weeks. NF-kappaB activation was increased by ethanol and associated with up-regulation of tumor necrosis factor alph a (TNF-alpha). These increases were blunted significantly up to 2 weeks by AdI kappaB-SR. Dietary alcohol significantly increased liver to body weight ratios and serum alanine transaminase (ALT) levels in AdlacZ-treated anima ls, effects that were blunted significantly in AdI kappaB-SR-treated rats. Ethanol caused severe steatosis, inflammation, and focal necrosis in AdlacZ -treated animals. These pathologic changes were significantly decreased by AdI kappaB-SR. The protective effects Of I kappaB-SR were significant 2 wee ks after injection, but were lost at 3 weeks when I kappaB-SR was no longer expressed. Ethanol increased 4-hydroxynonenal as a maker of oxidative stre ss in both AdlacZ and AdI kappaB groups. These data support the hypothesis that NF-kappaB inhibition prevents early alcohol-induced liver injury even in the presence of oxidative stress.