Prevention of hepatic ischemia-reperfusion injury by pre-administration of catalase-expressing adenovirus vectors.
Liver ischemia/reperfusion (I/R) injury, which is mainly caused by the generation of reactive oxygen species (ROS) during the reperfusion, remains an important clinical problem associated with liver transplantation and major liver surgery. Therefore, ROS should be detoxified to prevent hepatic I/R-induced injury. Delivery of antioxidant genes into liver is considered to be promising for prevention of hepatic I/R injury; however, therapeutic effects of antioxidant gene transfer to the liver have not been fully examined. The aim of this study was to examine whether adenovirus (Ad) vector-mediated catalase gene transfer in the liver is an effective approach for scavenging ROS and preventing hepatic I/R injury. Intravenous administration of Ad vectors expressing catalase, which is an antioxidant enzyme scavenging H(2)O(2), resulted in a significant increase in catalase activity in the liver. Pre-injection of catalase-expressing Ad vectors dramatically prevented I/R-induced elevation in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and hepatic necrosis. The livers were also protected in another liver injury model, CCl(4)-induced liver injury, by catalase-expressing Ad vectors. Furthermore, the survival rates of mice subjected to both partial hepatectomy and I/R treatment were improved by pre-injection of catalase-expressing Ad vectors. On the other hand, control Ad vectors expressing beta-galactosidase did not show any significant preventive effects in the liver on the models of I/R-induced or CCl(4)-induced hepatic injury described above. These results indicate that hepatic delivery of the catalase gene by Ad vectors is a promising approach for the prevention of oxidative stress-induced liver injury.
Ushitora
Masahiro
M
Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Osaka, Japan.
Sakurai
Fuminori
F
Yamaguchi
Tomoko
T
Nakamura
Shin-ichiro
S
Kondoh
Masuo
M
Yagi
Kiyohito
K
Kawabata
Kenji
K
Mizuguchi
Hiroyuki
H
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride; D002374:Catalase / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D056945:Hep G2 Cells; D006498:Hepatectomy; D008099:Liver / Q000098:blood supply* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D051379:Mice; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014162:Transfection
D017382:Reactive Oxygen Species; D002251:Carbon Tetrachloride; D002374:Catalase