Delivery of I[kappa ]B 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 B (NF-B) 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-B inhibition would prevent early alcohol-induced liver injury. Adenoviral vectors encoding either the transgene for IB superrepressor (AdIB-SR) or the bacterial ␤-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. IB-SR expression was increased for up to 2 weeks after injection, but was undetectable at 3 weeks. NF-B activation was increased by ethanol and associated with up-regulation of tumor necrosis factor ␣ (TNF-␣). These increases were blunted significantly up to 2 weeks by AdIB-SR. Dietary alcohol significantly increased liver to body weight ratios and serum alanine transaminase (ALT) levels in AdlacZtreated animals, effects that were blunted significantly in AdIB-SR-treated rats. Ethanol caused severe steatosis, inflammation, and focal necrosis in AdlacZ-treated animals. These pathologic changes were significantly decreased by AdIB-SR. The protective effects of IB-SR were significant 2 weeks after injection, but were lost at 3 weeks when IB-SR was no longer expressed. Ethanol increased 4-hydroxynonenal as a maker of oxidative stress in both AdlacZ and AdIB groups. These data support the hypothesis that NF-B inhibition prevents early alcohol-induced liver injury even in the presence of oxidative stress. (HEPATOLOGY 2001; 34:1149-1157.)

The Molecular Mechanisms of the Hepatoprotective Effect of Gomisin A against Oxidative Stress and Inflammatory Response in Rats with Carbon Tetrachloride-Induced Acute Liver Injury

“…26,29) It has been reported that it would be highly desirable to develop a pharmacological strategy to suppress the activation of NF-κB. 30,31) In the present work, gomisin A remarkably suppressed p-IκB and NF-κB expression following acute liver injury. This is the first report to show that gomisin A inhibited the activation of NF-κB, which may be associated with a reduction in the phosphorylation of IκB.…”

CYP2E1 potentiation of LPS and TNFα-induced hepatotoxicity by mechanisms involving enhanced oxidative and nitrosative stress, activation of MAP kinases, and mitochondrial dysfunction

“…Endotoxin activates NF-kB, leading to the hypothesis that inhibition of NF-kB in Kupffer cells would prevent ALD [90]. Administration of an adenovirus encoding for the IkB superrepressor to rats chronically infused with ethanol blunted the ethanol-induced activation of NF-kB, TNFa production, and pathological changes.…”

Selective inactivation of NF-κB in the liver using NF-κB decoy suppresses CCl4-induced liver injury and fibrosis

“…Some reports have indicated that hepatic injury induced by ischemia-reperfusion, alcohol, or endotoxin can be ameliorated by suppressing NF-B activation in the liver, especially in liver macrophages (14,33,35,36). However, whether selective and direct inactivation of NF-B in liver macrophages can suppress CCl 4 -induced liver injury or fibrosis has been unclear so far, whereas nonspecific inactivation of hepatic NF-B by some NF-B inhibitors has been reported to be antifibrogenic (6,26).…”