一氧化氮和超氧化物在大鼠急性异体心脏移植排斥反应中的作用。

E. Akizuki, T. Akaike, S. Okamoto, Shigemoto Fujii, Y. Yamaguchi, M. Ogawa, H. Maeda
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引用次数: 26

摘要

采用体外器官灌注系统研究了NO和超氧化物(O(2)(-))在同种异体心脏移植排斥反应中组织损伤中的作用。通过电子自旋共振光谱和Northern blotting检测,同种异体心脏移植物在心脏移植后5天观察到过量的NO产生和诱导NO合成酶(iNOS)表达,而在心脏同种异体移植物中则没有。移植后第5天获得的心脏同种异体或同种异体移植物灌注碳酸氢盐Krebs缓冲液,含或不含各种NO或O(2)-解毒剂,包括N(omega)-单甲基- l-精氨酸(L-NMMA);1 mM), 2-苯基- 4,4,5,5 -四甲基咪唑-1-氧基- 3-氧化物(PTIO;100微米),4-氨基-6-羟基吡唑[3,4-d]嘧啶(AHPP;黄嘌呤氧化酶抑制剂;100微米),超氧化物歧化酶(SOD;100单位/毫升)。同种异体心脏移植物经PTIO处理后,灌注液中天冬氨酸转氨酶、乳酸脱氢酶和肌酸磷酸激酶浓度显著降低,对心脏损伤的改善最为显著。L-NMMA、AHPP和SOD对同种异体移植物损伤的保护作用相似,但作用较弱。免疫组化iNOS和硝基酪氨酸分析表明,iNOS主要通过浸润同种异体移植物组织的巨噬细胞表达,并且硝基酪氨酸不仅在巨噬细胞中形成,而且在同种异体移植物的心肌细胞中也存在,这为同种异体移植物排斥反应中过氧亚硝酸盐的产生提供了间接证据。我们的研究结果表明,大鼠同种异体心脏移植在急性排斥反应期间的组织损伤是由NO和O(2)(-)介导的,可能是通过过氧亚硝酸盐的形成。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Role of nitric oxide and superoxide in acute cardiac allograft rejection in rats.
The role of NO and superoxide (O(2)(-)) in tissue injury during cardiac allograft rejection was investigated by using a rat ex vivo organ perfusion system. Excessive NO production and inducible NO synthase (iNOS) expression were observed in cardiac allografts at 5 days after cardiac transplantation, but not in cardiac isografts, as identified by electron spin resonance spectroscopy and Northern blotting. Cardiac isografts or allografts obtained on Day 5 after transplantation were perfused with Krebs bicarbonate buffer with or without various antidotes for NO or O(2)-, including N(omega)-monomethyl-L-arginine (L-NMMA; 1 mM), 2-phenyl-4,4,5, 5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO; 100 microM), 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP; a xanthine oxidase inhibitor; 100 microM), and superoxide dismutase (SOD; 100 units/ml). Treatment of the cardiac allografts with PTIO showed most remarkable improvement of the cardiac injury as revealed by significant reduction in aspartate transaminase, lactate dehydrogenase, and creatine phosphokinase concentrations in the perfusate. Similar but less potent protective effect on the allograft injury was observed by treatment with L-NMMA, AHPP, and SOD. Immunohistochemical analyses for iNOS and nitrotyrosine indicated that iNOS is mainly expressed by macrophages infiltrating the allograft tissues, and nitrotyrosine formation was demonstrated not only in macrophages but also in cardiac myocytes of the allografts, providing indirect evidence for the generation of peroxynitrite during allograft rejection. Our results suggest that tissue injury in rat cardiac allografts during acute rejection is mediated by both NO and O(2)(-), possibly through peroxynitrite formation.
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