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DELIVERY OF ANTIOXIDATIVE ENZYME GENES PROTECTS AGAINST ISCHEMIA/REPERFUSION-INDUCED LIVER INJURY IN MICE

Abstract

BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is characterized by the generation of reactive oxygen species (ROS), such as superoxide anions and hydrogen peroxide. The aim of this study is to investigate whether anti-oxidative gene delivery by our polylipid nanoparticles (PLNP) is an effective approach for prevention of the injury. METHODS: Polyplexes of extracellular superoxide dismutase (EC-SOD) and/or catalase genes were injected via the portal vein one day prior to a warm I/R procedure in mice. The effects of the gene delivery were determined 6 hours after starting reperfusion. RESULTS: PLNP-mediated anti-oxidative gene delivery led to a marked increase in human EC-SOD and catalase gene expression in the liver. Liver SOD and catalase activity both increased approximately 10 fold. Increased liver superoxide anion levels caused by the I/R procedure were reduced to normal levels by EC-SOD gene delivery. The overexpression of these two anti-oxidative genes significantly suppressed the I/R-induced elevation of serum alanine aminotransferase levels, decreased liver malondialdehyde content, restored glutathione reserve, and improved liver histology. CONCLUSION: EC-SOD or catalase gene delivery by PLNP resulted in high levels of the transgene activity in the liver, and markedly attenuated hepatic I/R injury. The protection is directly associated with elevated anti-oxidative enzyme activity as the result of the gene delivery. This novel approach may become a potential therapy to improve graft function and survival after liver transplantation.

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