Minimizing oxidative stress by gene delivery of superoxide dismutase accelerates regeneration after transplantation of reduced-size livers in the rat.
Transplantation of reduced-size livers may lead to a hypermetabolic state and increased production of oxygen radicals. Since oxygen radicals may cause liver injury and impair liver regeneration, we tested the hypothesis that overexpression of superoxide dismutase (SOD) in reduced-size livers (RSL) would accelerate regeneration and reduce injury in a rat model of transplantation of RSL. Donor rats were infected with adenoviruses either expressing SOD1 (Ad.SOD1) or beta-galactosidase (Ad.lacZ). Livers were harvested 72 hours later, reduced to 45% of weight, and transplanted. After transplantation, hepatic SOD activity, graft survival, histopathology, AST/ALT release, and bilirubin were examined. Regeneration was evaluated by BrdU-staining, graft weight, and expression of cyclin D1 and p21. In Ad.SOD1-treated livergrafts, SOD activity increased three-fold compared to controls. Survival was dramatically increased in recipients of Ad.SOD1-RSL (100% vs. 20% in Ad.lacZ-RSL), and peak levels of AST/ALT and bilirubin levels were reduced by 75% and 87.5%, respectively (P < 0.001). In histological sections, hepatocyte necrosis decreased from 24% after Ad.lacZ-treatment to 6% after Ad.SOD1-treatment (P <0.001). Regeneration was also accelerated after Ad.SOD1-treatment as demonstrated by an increase of BrdU-stained cells 24 hours after reperfusion and increased liver weight after 1 week. In conclusion, overexpression of SOD1 in RSL prevents primary non-function of reduced-size liver grafts and accelerates liver regeneration.
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Thorsten G
TG
Lehmann
Tom
T
Luedde
Robert F
RF
Schwabe
Hartwig
H
Bunzendahl
R Jude
RJ
Samulski
John J
JJ
Lemasters
David A
DA
Brenner
D000256:Adenoviridae; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D005822:Genetic Vectors; D008115:Liver Regeneration; D016031:Liver Transplantation; D023421:Models, Animal; D009929:Organ Size; D018384:Oxidative Stress; D011168:Portal System; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014162:Transfection; D016896:Treatment Outcome; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D001616:beta-Galactosidase