Delivery of antioxidative enzyme genes protects against ischemia/reperfusion-induced liver injury in mice
Delivery of antioxidative enzyme genes protects against ischemia/reperfusion-induced liver injury in mice
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DOI：
10.1002/lt.21001
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发表时间：
2006-12-01
影响因子：
4.6
通讯作者：
Wu, Jian
中科院分区：
文献类型：
--
作者：
He, Song-Qing;Zhang, Yan-Hong;Wu, Jian
肝缺血/再灌注损伤的特征是产生活性氧，如超氧阴离子和过氧化氢。本研究的目的是调查我们的多脂纳米颗粒（PLNP）的抗氧化基因传递是否是一种有效的方法，用于预防损伤。细胞外超氧化物歧化酶（EC-SOD）和/或过氧化氢酶基因的复合物通过门静脉注射前1天，在小鼠中的一个温暖的I/R程序。在开始再灌注后6小时测定基因递送的效果。PLNP介导的抗氧化基因传递导致人EC-SOD和过氧化氢酶基因在肝脏中的表达显著增加。肝脏超氧化物歧化酶（SOD）和过氧化氢酶活性均增加约10倍。增加肝脏超氧阴离子水平所造成的I/R程序减少到正常水平的EC-SOD基因传递。这2个抗氧化基因的过表达显著抑制I/R诱导的血清丙氨酸氨基转移酶（ALT）水平升高，降低肝脏丙二醛含量，恢复谷胱甘肽储备，并改善肝脏组织学。总之，通过PLNP的EC-SOD或过氧化氢酶基因递送导致肝脏中高水平的转基因活性，并显著减弱肝脏I/R损伤。这种保护作用与基因传递导致的抗氧化酶活性升高直接相关。这种新的方法可能成为一种潜在的治疗，以改善移植物功能和肝移植后的生存。
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 antioxidative gene delivery by our polylipid nanoparticles (PLNP) is an effective approach for prevention of the injury. Polyplexes of extracellular superoxide dismutase (EC-SOD) and/or catalase genes were injected via the portal vein 1 day prior to a warm I/R procedure in mice. The effects of the gene delivery were determined 6 hours after starting reperfusion. PLNP-mediated antioxidative gene delivery led to a marked increase in human EC-SOD and catalase gene expression in the liver. Liver superoxide dismutase (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 2 antioxidative genes significantly suppressed the I/R-induced elevation of serum alanine aminotransferase (ALT) levels, decreased liver malondialdehyde content, restored glutathione reserve, and improved liver histology. In 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 antioxidative 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.