Role of nitric oxide in hepatic ischemia-reperfusion with endotoxemia.
Role of nitric oxide in hepatic ischemia-reperfusion with endotoxemia.
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发表时间：
1995
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通讯作者：
P. Liu;Khin Nyein Yin;G. Yue;P. Wong
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作者：
P. Liu;Khin Nyein Yin;G. Yue;P. Wong
活性氧如一氧化氮（NO）和/或超氧化物被认为是再灌注损伤和急性内毒素血症发病机制的介质。本研究的目的是研究NO在肝缺血再灌注伴内毒素血症（I/R + LPS）模型中的作用。大鼠局部肝缺血30分钟后再灌注LPS（肠炎沙门氏菌，1 mg/kg，静脉注射），与假药对照组相比，血浆丙氨酸转氨酶（ALT）水平出现明显的时间依赖性升高。在I/R + LPS大鼠中，肝脏亚硝酸盐/硝酸盐水平的突然增加与血浆ALT的增加有关。尽管I/R + LPS大鼠的肝脏NO产量随着时间的推移而增加，但肝损伤的加剧并不明显。L-NAME可降低I/R + LPS大鼠血浆和肝脏NO的生成，但对肝损伤无影响。I/R + LPS大鼠肝脏超氧化物水平在再灌注90分钟后增加了三倍，但在4小时后下降到对照水平。与假对照组和接受LPS治疗的非缺血肝叶相比，缺血再灌注和LPS治疗的肝叶中中性粒细胞显著增加。给予L-NAME的大鼠肝脏中中性粒细胞的数量进一步增加。这些结果表明，I/R + LPS大鼠肝脏的进行性损伤可能是由于NO与超氧化物相互作用形成另一种活性氧，如过氧亚硝酸盐。然而，抑制NO合成并不能改善肝损伤，这可能是因为活化的多形核白细胞（PMN）的组织积累增加。再灌注4小时后，与假对照组相比，I/R + LPS大鼠肺NO生成增加。先前给予L-NAME并不能阻止肺NO生成的显著增加（与假对照组相比，在90分钟和4小时时P < 0.05）。L-NAME处理组大鼠肺NO的意外升高与PMN积累（基于髓过氧化物酶数据）和超氧化物生成增加的趋势有关。结果提示，内源性NO对肝缺血再灌注内毒素血症模型肺内嗜中性粒细胞过度浸润具有保护作用，而非选择性NOS抑制剂L-NAME的使用可能加重肺损伤。
Reactive oxygen species such as nitric oxide (NO) and/or superoxide have been proposed as mediators in the pathogenesis of reperfusion injury and acute endotoxemia. The purpose of this study was to examine the role of NO in a model of hepatic ischemia-reperfusion with endotoxemia (I/R + LPS). Rats subjected to 30 min of partial hepatic ischemia followed by reperfusion and LPS (Salmonella enteritidis, 1 mg/kg, i.v.,) administration, exhibited a marked, time-dependent increase in plasma alanine aminotransferase (ALT) levels compared to sham controls. An abrupt increase in liver nitrite/nitrate levels was also observed in I/R + LPS rats in association with the increases in plasma ALT. Although liver NO production in I/R + LPS rats increased with time, exacerbation of liver damage was not evident. Administration of L-NAME decreased NO production in plasma and liver but did not affect the liver damage in rats subjected to I/R + LPS. Superoxide levels in livers from I/R + LPS rats increased by threefold after 90 min reperfusion as compared to sham controls but dropped to control levels after 4 hr. There was a significant increase in neutrophils in liver lobes subjected to ischemia-reperfusion and LPS compared to sham controls and to non-ischemic lobes which received LPS. The number of neutrophils in the liver increased further in rats given L-NAME. These results suggest that the progressive injury seen in livers of I/R + LPS rats was possibly due to NO interaction with superoxide forming another reactive oxygen species such as peroxynitrite. However, inhibition of NO synthesis did not ameliorate liver damage, possibly because of an increase in tissue accumulation of activated polymorphonuclear leukocytes (PMN). Lung NO production increased in I/R + LPS rats after 4 hr reperfusion compared to sham controls. Prior administration of L-NAME did not prevent a significant rise in pulmonary NO generation (P < 0.05 at 90 min and 4 hr, compared to sham controls). This unexpected rise of pulmonary NO in the L-NAME treated group of rats was associated with a tendency for increased PMN accumulation (based on myeloperoxidase data) and superoxide generation. The results suggest that endogenous NO protected against excessive neutrophil infiltration in the lung in this model of hepatic ischemia-reperfusion and endotoxemia, and the use of L-NAME, a nonselective NOS inhibitor, may aggravate lung injury.