Liposome-mediated extracellular superoxide dismutase gene delivery protects against acute liver injury in mice.
Our previous study demonstrated that polycationic liposomes are highly stable in the bloodstream and represent an effective agent for liver gene delivery. We report here that liposome-mediated extracellular superoxide dismutase (EC-SOD) gene delivery successfully prevented acute liver injury in mice. The therapeutic efficacy of EC-SOD gene delivery by polycationic liposomes was determined against the toxicity of superoxide anions and hydroxyethyl radicals in HepG2 cells and in a mouse model of acute liver injury caused by D-galactosamine and lipopolysaccharide intoxication. Transfection of HepG2 cells with an EC-SOD plasmid led to a striking increase in superoxide dismutase activity in the medium. The transfected cells had much less cell death after reactive oxygen species exposure compared with untransfected or control plasmid-transfected cells. In a model of acute liver injury, serum alanine aminotransferase levels in mice receiving portal vein injections of EC-SOD lipoplexes were much lower than in those receiving normal saline, liposomes alone, or control lipoplexes. Liver histology confirmed that there was less cell death in the EC-SOD lipoplex-treated group. Quantitative reverse transcriptase polymerase chain reaction showed a 55-fold increase in human EC-SOD gene expression in the liver of mice injected with EC-SOD lipoplexes. Serum superoxide dismutase activity in EC-SOD lipoplex-treated mice was higher than in the control groups; this was associated with higher liver glutathione levels and reduced lipid peroxidation. In conclusion, polycationic liposome-mediated EC-SOD gene delivery protects against reactive oxygen species toxicity in vitro and against lipopolysaccharide-induced acute liver injury in D-galactosamine-sensitized mice.
Wu
Jian
J
Transplant Research Institute, University of California-Davis Medical Center, Sacramento, 95817, USA. jdwu@ucdavis.edu
Liu
Li
L
Yen
Roy D
RD
Catana
Andreea
A
Nantz
Michael H
MH
Zern
Mark A
MA
D000208:Acute Disease; D000818:Animals; D002412:Cations; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury; D002784:Cholesterol; D003470:Culture Media / Q000737:chemistry; D000431:Ethanol / Q000506:poisoning; D045604:Extracellular Fluid / Q000201:enzymology*; D018014:Gene Transfer Techniques; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008055:Lipids; D008070:Lipopolysaccharides / Q000506:poisoning; D008081:Liposomes; D008099:Liver / Q000187:drug effects; D008107:Liver Diseases / Q000517:prevention & control*; D051379:Mice; D010957:Plasmids; D013482:Superoxide Dismutase / Q000032:analysis / Q000235:genetics* / Q000494:pharmacology; D013481:Superoxides / Q000506:poisoning; D014162:Transfection
D002412:Cations; D003470:Culture Media; D008055:Lipids; D008070:Lipopolysaccharides; D008081:Liposomes; D013481:Superoxides; C065424:1-hydroxyethyl radical; D000431:Ethanol; D002784:Cholesterol; D013482:Superoxide Dismutase; D005978:Glutathione