Delivery of IkappaB superrepressor gene with adenovirus reduces early alcohol-induced liver injury in rats.
Chronic alcohol administration increases gut-derived endotoxin in the portal blood, which activates Kupffer cells through nuclear factor kappaB (NF-kappaB) 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-kappaB inhibition would prevent early alcohol-induced liver injury. Adenoviral vectors encoding either the transgene for IkappaB superrepressor (AdIkappaB-SR) or the bacterial beta-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. IkappaB-SR expression was increased for up to 2 weeks after injection, but was undetectable at 3 weeks. NF-kappaB activation was increased by ethanol and associated with up-regulation of tumor necrosis factor alpha (TNF-alpha). These increases were blunted significantly up to 2 weeks by AdIkappaB-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 AdIkappaB-SR-treated rats. Ethanol caused severe steatosis, inflammation, and focal necrosis in AdlacZ-treated animals. These pathologic changes were significantly decreased by AdIkappaB-SR. The protective effects of IkappaB-SR were significant 2 weeks after injection, but were lost at 3 weeks when IkappaB-SR was no longer expressed. Ethanol increased 4-hydroxynonenal as a maker of oxidative stress in both AdlacZ and AdIkappaB groups. These data support the hypothesis that NF-kappaB inhibition prevents early alcohol-induced liver injury even in the presence of oxidative stress.
Uesugi
T
T
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599-7365, USA.
Froh
M
M
Arteel
G E
GE
Bradford
B U
BU
Gäbele
E
E
Wheeler
M D
MD
Thurman
R G
RG
D000256:Adenoviridae / Q000235:genetics*; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D016207:Cytokines / Q000235:genetics; D000431:Ethanol / Q000652:urine; D015870:Gene Expression; D005822:Genetic Vectors; D020672:I-kappa B Proteins / Q000235:genetics* / Q000378:metabolism; D018836:Inflammation Mediators / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000502:physiology; D009929:Organ Size; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000447:Aldehydes; D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D000637:Transaminases; C027576:4-hydroxy-2-nonenal