Study of the mechanism of liver ischemia-repeifusion injuiy based on modulation of NF-kB activation by gene transfer technique

NF-κ B是一种普遍存在的转录因子，参与多种炎症反应的上调。我们最近发现，在肝缺血再灌注和内毒素诱导的休克肝中，NF-κ B活性增加。本研究旨在探讨NF-kB decoy是否能通过抑制内毒素休克或急性肝排斥反应模型中NF-kB的活化来抑制促炎基因的上调，从而提高动物的存活率。门静脉注射NF-kB诱饵治疗显著增加了脂多糖注射后24和48小时的存活率，并抑制了血浆TNF-α活性的增加。NF-kB诱饵处理对过氧化氢诱导的Jurkat细胞中NF-kB活化具有抑制作用。在大鼠肝移植的急性肝排斥模型（供体; DA大鼠，受体;刘易斯大鼠）中，用保存液中的NF-κ B诱饵处理显著抑制了炎性细胞因子mRNA的表达，并增加了受体大鼠的存活率。提示NF-κ B decoy可通过抑制NF-κ B的活化而抑制促炎细胞因子的上调，是治疗内毒素休克和急性肝排斥反应的一种有前景的新药。

The NF-kB is a ubiquitous transcriptional factor involved in the up-regulation of many inflammatory response. We recently demonstrated that NF-kB activity increased during the hepatic ischemia-reperfusion and endotoxin induced shock liver. The present study was undertaken to determine whether NF-kB decoy could suppress proinflammatory gene up-regulation through inhibition of NF-kB activation in endotoxin shock or acute liver rejection model and increase the survival rate of animals. Treatment with NF-kB decoy injected in the portal vein significantly increased survival rates 24 and 48 hours after lipopolysaccharide injection and suppressed the increase of plasma TNF-alpha activity. NF-kB decoy treatment showed inhibitory effect on hydrogen peroxide induced NF-kB activation in Jurkat cells. in the acute liver rejection model in the rat liver transplantation (donor ; DA rats, recipient ; Lewis rats), treatment with NF-kB decoy in the preservation fluid significantly suppressed expression of inflammatory cytokine mRNA and increased the survival rate of the recipient rats. These results suggest that NF-kB decoy can suppress proinflammatory cytokine up-regulation through inhibition of NF-kB activation and it is a promising new drug for the treatment of endotoxin shock and acute liver rejection.