Delivery of IκB superrepressor gene with adenovirus reduces early alcohol-induced liver injury in rats

Abstract

Chronic alcohol administration increases gut-derived endotoxin in the portal blood, which activates Kupffer cells through nuclear factor κB (NF-κB) to produce toxic mediators such as proinflammatory cytokines, leading to liver injury. Therefore, a long-term intragastric ethanol feeding protocol was used here to test the hypothesis that NF-κB inhibition would prevent early alcohol-induced liver injury. Adenoviral vectors encoding either the transgene for IκB superrepressor (AdIκB-SR) or the bacterial β-galactosidase reporter gene (AdlacZ) were administered intravenously to Wistar rats. Animals were fed a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin (control) for 3 weeks. There was no significant difference in mean urine alcohol concentrations between the groups fed ethanol. IκB-SR expression was increased for up to 2 weeks after injection, but was undetectable at 3 weeks. NF-κB activation was increased by ethanol and associated with up-regulation of tumor necrosis factor α(TNF-α). These increases were blunted significantly up to 2 weeks by AdIκB-SR. Dietary alcohol significantly increased liver to body weight ratios and serum alanine transaminase (ALT) levels in AdlacZ-treated animals, effects that were blunted significantly in AdIκB-SR-treated rats. Ethanol caused severe steatosis, inflammation, and focal necrosis in AdlacZ-treated animals. These pathologic changes were significantly decreased by AdIκB-SR. The protective effects of IκB-SR were significant 2 weeks after injection, but were lost at 3 weeks when IκB-SR was no longer expressed. Ethanol increased 4-hydroxynonenal as a maker of oxidative stress in both AdlacZ and AdIκB groups. These data support the hypothesis that NF-κB inhibition prevents early alcohol-induced liver injury even in the presence of oxidative stress.