Delivery of the Cu/Zn-superoxide dismutase gene with adenovirus reduces early alcohol-induced liver injury in rats.
OBJECTIVE
Alcohol-induced liver injury is associated with an increase in oxidants from a variety of possible sources. Therefore, it was hypothesized that increased and stable expression of the antioxidant enzyme Cu/Zn-superoxide dismutase (SOD1) would diminish oxygen free radicals and reduce alcohol-induced liver injury.


METHODS
To test this hypothesis, rats were given recombinant adenovirus containing Cu/Zn-superoxide dismutase (Ad.SOD1) or beta-galactosidase (Ad.lacZ) and fed ethanol enterally for 3 weeks.


RESULTS
SOD was increased significantly 3-5-fold over endogenous levels in both hepatocytes as well as Kupffer cells 3 weeks after infection. Serum transaminase levels and pathology were elevated significantly in Ad.lacZ-treated animals by using an intragastric feeding model. This effect was blunted significantly in Ad.SOD1-infected animals. Importantly, electron spin resonance-detectable free-radical adducts caused by ethanol were also decreased by SOD1 overexpression. Moreover, the increase in nuclear factor kappaB (NFkappaB), tumor necrosis factor alpha (TNF-alpha), and interleukin 1 messenger RNA (mRNA) caused by ethanol was blunted in animals treated with Ad.SOD1.


CONCLUSIONS
These data support the hypothesis that oxidant production is critical in early alcohol-induced liver injury and that gene delivery of antioxidant enzymes may be useful in prevention and treatment.
Wheeler
M D
MD
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. wheelmi@med.unc.edu
Kono
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Yin
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Rusyn
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Froh
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Connor
H D
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Mason
R P
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Samulski
R J
RJ
Thurman
R G
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D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy / Q000379:methods*; D007375:Interleukin-1 / Q000235:genetics; D008108:Liver Diseases, Alcoholic / Q000628:therapy*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000235:genetics*; D019076:Transgenes / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D002492:Central Nervous System Depressants; D005609:Free Radicals; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D013482:Superoxide Dismutase