Liu P, Yin K, Yue G, Wong P Y
Department of Cell Biology, University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, Stratford 08084, USA.
J Inflamm. 1995;46(3):144-54.
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.
诸如一氧化氮（NO）和/或超氧化物等活性氧已被认为是再灌注损伤和急性内毒素血症发病机制中的介质。本研究的目的是研究NO在伴有内毒素血症的肝脏缺血再灌注模型（I/R + LPS）中的作用。与假手术对照组相比，经历30分钟部分肝脏缺血然后再灌注并给予LPS（肠炎沙门氏菌，1mg/kg，静脉注射）的大鼠，血浆丙氨酸转氨酶（ALT）水平呈现出明显的、时间依赖性的升高。在I/R + LPS大鼠中还观察到肝脏亚硝酸盐/硝酸盐水平与血浆ALT升高相关的突然增加。尽管I/R + LPS大鼠肝脏中的NO生成随时间增加，但肝损伤的加重并不明显。给予L-NAME可降低血浆和肝脏中的NO生成，但不影响I/R + LPS大鼠的肝损伤。与假手术对照组相比，I/R + LPS大鼠肝脏中的超氧化物水平在再灌注90分钟后增加了三倍，但在4小时后降至对照水平。与假手术对照组以及接受LPS的非缺血叶相比，经历缺血再灌注和LPS的肝叶中的中性粒细胞显著增加。给予L-NAME的大鼠肝脏中的中性粒细胞数量进一步增加。这些结果表明，I/R + LPS大鼠肝脏中出现的进行性损伤可能是由于NO与超氧化物相互作用形成了另一种活性氧，如过氧亚硝酸盐。然而，抑制NO合成并不能改善肝损伤，可能是因为活化的多形核白细胞（PMN）在组织中的积累增加。与假手术对照组相比，I/R + LPS大鼠再灌注4小时后肺中的NO生成增加。预先给予L-NAME并不能阻止肺中NO生成的显著升高（与假手术对照组相比，90分钟和4小时时P < 0.05）。L-NAME处理组大鼠肺中NO的这种意外升高与PMN积累增加（基于髓过氧化物酶数据）和超氧化物生成的趋势相关。结果表明，在这种肝脏缺血再灌注和内毒素血症模型中，内源性NO可防止肺中过度的中性粒细胞浸润，而使用非选择性NOS抑制剂L-NAME可能会加重肺损伤。
