Hines I N, Harada H, Bharwani S, Pavlick K P, Hoffman J M, Grisham M B
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA.
Biochem Biophys Res Commun. 2001 Jun 22;284(4):972-6. doi: 10.1006/bbrc.2001.5069.
The objective of this study was to assess the role of inducible nitric oxide synthase (iNOS) in ischemia- and reperfusion (I/R)-induced liver injury. We found that partial hepatic ischemia involving 70% of the liver resulted in a time-dependent increase in serum alanine aminotransferase (ALT) levels at 1-6 h following reperfusion. Liver injury at 1, 3, and 6 h post-ischemia was not due to the infiltration of neutrophils as assessed by tissue myeloperoxidase (MPO) activity and histopathology. iNOS-deficient mice subjected to the same duration of ischemia and reperfusion showed dramatic and significant increases in liver injury at 3 but not 6 h following reperfusion compared to their wild type controls. Paradoxically, iNOS mRNA expression was not detected in the livers of wild type mice at any point during the reperfusion period and pharmacological inhibition of iNOS using L-N(6)(iminoethyl)-lysine (L-NIL) did not exacerbate post-ischemic liver injury at any time post-reperfusion. These data suggest that iNOS deficiency produces unanticipated genetic alterations that renders these mice more sensitive to liver I/R-induced injury.
本研究的目的是评估诱导型一氧化氮合酶（iNOS）在缺血再灌注（I/R）诱导的肝损伤中的作用。我们发现，涉及70%肝脏的部分肝缺血导致再灌注后1-6小时血清丙氨酸氨基转移酶（ALT）水平呈时间依赖性升高。通过组织髓过氧化物酶（MPO）活性和组织病理学评估，缺血后1、3和6小时的肝损伤并非由于中性粒细胞浸润所致。与野生型对照相比，经历相同缺血和再灌注时间的iNOS缺陷小鼠在再灌注后3小时而非6小时显示出肝损伤显著大幅增加。矛盾的是，在再灌注期间的任何时间点，野生型小鼠肝脏中均未检测到iNOS mRNA表达，并且使用L-N(6)(亚氨基乙基)-赖氨酸（L-NIL）对iNOS进行药理学抑制在再灌注后的任何时间均未加重缺血后肝损伤。这些数据表明，iNOS缺陷产生了意想不到的基因改变，使这些小鼠对肝I/R诱导的损伤更敏感。
