Takamatsu Yuji, Shimada Kazuo, Yamaguchi Koji, Kuroki Syoji, Chijiiwa Kazuo, Tanaka Masao
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Dig Dis Sci. 2006 Mar;51(3):571-9. doi: 10.1007/s10620-006-3172-5.
The aim of this study was to investigate the contribution of inducible nitric oxide synthase (iNOS)-derived nitric oxide on the liver and lung injury following hepatic ischemia-reperfusion (I/R) using a novel and potent iNOS inhibitor, ONO-1714. Rats were subjected to 90 min of partial hepatic ischemia followed by 3, 6, 12, and 24 hr of reperfusion. Expression of iNOS mRNA peaked at 3 hr of reperfusion in the liver and lung. Plasma nitric oxide levels were increased fourfold at 24 hr of reperfusion and plasma ALT was increased, reaching a peak at 12 hr of reperfusion; both were significantly inhibited by ONO-1714. Histological examination revealed extensive liver damage, whereas this was not seen in the ONO-1714 group. Lung injury was not significantly changed in groups with versus without ONO-1714. Nitrotyrosine expression was seen in regions similar to those of the histological injuries of the liver, while this staining was absent in the ONO-1714 group. These data show that generation of peroxynitrite could be involved in the pathogenesis of liver injury but not lung injury after hepatic I/R. Inhibition of iNOS could be applied for attenuation of liver injury following hepatic I/R.
本研究旨在使用新型强效诱导型一氧化氮合酶（iNOS）抑制剂ONO-1714，探讨iNOS衍生的一氧化氮对肝缺血再灌注（I/R）后肝脏和肺损伤的作用。对大鼠进行90分钟的部分肝缺血，然后再灌注3、6、12和24小时。iNOS mRNA的表达在肝脏和肺再灌注3小时时达到峰值。再灌注24小时时血浆一氧化氮水平增加了四倍，血浆谷丙转氨酶（ALT）升高，在再灌注12小时时达到峰值；两者均被ONO-1714显著抑制。组织学检查显示肝脏有广泛损伤，而在ONO-1714组中未观察到这种情况。有无ONO-1714的组中肺损伤均无明显变化。硝基酪氨酸表达出现在与肝脏组织学损伤相似的区域，而在ONO-1714组中没有这种染色。这些数据表明，过氧亚硝酸盐的产生可能参与肝I/R后肝损伤的发病机制，但不参与肺损伤。抑制iNOS可用于减轻肝I/R后的肝损伤。
