Prevention of neutrophil-mediated hepatic ischemia/reperfusion injury by superoxide dismutase and catalase derivatives.
Prevention of neutrophil-mediated hepatic ischemia/reperfusion injury by superoxide dismutase and catalase derivatives.
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发表时间：
2001-09
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通讯作者：
Y. Yabe;Naoki Kobayashi;Tsuyoshi Nishihashi;R. Takahashi;M. Nishikawa;Y. Takakura;M. Hashida
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作者：
Y. Yabe;Naoki Kobayashi;Tsuyoshi Nishihashi;R. Takahashi;M. Nishikawa;Y. Takakura;M. Hashida
我们以前的研究表明，甘露糖超氧化物歧化酶（Man-SOD）和琥珀酰化过氧化氢酶（Suc-CAT），这两种酶的目的是针对肝脏非实质细胞的组合，是一种有前途的方法，以防止肝缺血/再灌注损伤的初始阶段诱导的门静脉闭塞30分钟，然后再灌注1小时的小鼠。在这项研究中，这些药物的预防作用进行了检查，对晚期损伤介导的浸润性中性粒细胞，一个更严重的条件比最初的。Suc-CAT单独或与Man-SOD一起给药于经历肝缺血/再灌注的小鼠显著抑制了沿着肝窦的细胞间粘附分子-1的表达，并防止了中性粒细胞在肝脏中的浸润。Man-SOD和Suc-CAT也能抑制再灌注3和6 h后血浆谷丙转氨酶和谷草转氨酶活性的升高。肝组织的组织学评价证实了这种治疗的有效性，表明这些SOD和过氧化氢酶衍生物具有抑制嗜酸性粒细胞诱导的肝损伤的能力。这些结果表明，抗氧化酶靶向输送到肝脏非实质细胞是一种有前途的方法，以减少由枯否细胞和中性粒细胞浸润到组织中产生的活性氧。由于Suc-CAT通过过氧化氢酶特异性摄取机制被肝细胞部分摄取，因此这一部分也可能参与其对损伤的预防作用。
Our previous study demonstrated that the combination of mannosylated superoxide dismutase (Man-SOD) and succinylated catalase (Suc-CAT), both of which are designed to be targeted to liver nonparenchymal cells, is a promising approach to prevent the initial phase of hepatic ischemia/reperfusion injury induced by occlusion of the portal vein for 30 min followed by a 1-h reperfusion in mice. In this study, the preventive effects of these agents were examined on late-phase injury mediated by infiltrating neutrophils, a more severe condition than the initial one. Administration of Suc-CAT alone or with Man-SOD to mice undergoing hepatic ischemia/reperfusion significantly suppressed the expression of intercellular adhesion molecule-1 along the hepatic sinusoid and prevented neutrophil infiltration in the liver. Man-SOD and Suc-CAT also prevented the increase in plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase activities after reperfusion lasting 3 and 6 h. Histological evaluation of liver tissues confirmed the efficacy of this treatment, suggesting that these SOD and catalase derivatives have the ability to suppress neutrophil-induced hepatic injury. These results demonstrate that targeted delivery of antioxidant enzymes to liver nonparenchymal cells is a promising approach to reducing the reactive oxygen species produced by Kupffer cells and neutrophils infiltrating into the tissue. Since Suc-CAT is partially taken up by hepatocytes via a catalase-specific uptake mechanism, such a fraction could also be involved in its preventive effect against the injury.