Lentivirus-mediated superoxide dismutase1 gene delivery protects against oxidative stress-induced liver injury in mice.
BACKGROUND
The exposure of liver to hepatotoxins, and their subsequent metabolism, results in increased reactive oxygen species (ROS), one of the major culprits in causing both acute liver cell injury and chronic liver diseases. The aim of this present study is to investigate the protective effects of lentiviral vector-mediated copper-zinc superoxide dismutase (LV-SOD1) gene transfer against ROS-induced cytotoxicity in Hep G2 cells and liver injury in mice.


METHODS
In vitro SOD1 efficacy was tested against two ROS-generating systems: hypoxanthine/xanthine oxidase (HX/XO) and hydroxyethyl radicals (HER), whereas in vivo SOD1 efficacy was evaluated in carbon tetrachloride (CCl4)-induced liver injury in C57BL/6 mice.


RESULTS
LV-SOD1 transduction in Hep G2 cells resulted in a significant increase in SOD activity in cell lysates, and it significantly decreased the toxicity induced by HX/XO and HER. High SOD1 expression in the liver was achieved via portal vein injection of LV-SOD1 in mice and these high levels were observed for 30 days, the length of the experiment to date. SOD1 overexpression significantly decreased the toxicity and restored liver function in the CCl4-treated mice.


CONCLUSIONS
These findings demonstrate for the first time that LV transduction led to the long-term expression of fully functional transgene expression in both in vitro and in vivo systems.
Department of Internal Medicine, Transplant Research Program, UC Davis Medical Center, Sacramento, CA 95817, USA.
Senthil Kumar
SK
Venugopal
Jian
J
Wu
Andreea M
AM
Catana
Lauren
L
Eisenbud
Song-Qing
SQ
He
Yu-You
YY
Duan
Antonia
A
Follenzi
Mark A
MA
Zern
D000208:Acute Disease; D000818:Animals; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002908:Chronic Disease; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008107:Liver Diseases / Q000378:metabolism / Q000628:therapy*; D008113:Liver Neoplasms; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D019076:Transgenes / Q000235:genetics
C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1