title: Liposome-mediated extracellular superoxide dismutase gene delivery protects against acute liver injury in mice.
abstract: 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.
authors.affiliation: Transplant Research Institute, University of California-Davis Medical Center, Sacramento, 95817, USA. jdwu@ucdavis.edu
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Roy D
authors.initials: RD
authors.lastname: Yen
authors.forename: Andreea
authors.initials: A
authors.lastname: Catana
authors.forename: Michael H
authors.initials: MH
authors.lastname: Nantz
authors.forename: Mark A
authors.initials: MA
authors.lastname: Zern
mesh_terms: 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
chemical_list: 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