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Delivery of IκB superrepressor gene with adenovirus reduces early alcohol‐induced liver injury in rats
Author(s) -
Uesugi Takehiko,
Froh Matthias,
Arteel Gavin E.,
Bradford Blair U.,
Gábele Erwin,
Wheeler Michael D.,
Thurman Ronald G.
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.29400
Subject(s) - proinflammatory cytokine , liquid diet , liver injury , medicine , ethanol , steatosis , endocrinology , tumor necrosis factor alpha , alcohol , inflammation , chemistry , biochemistry
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.