Role of xanthine oxidoreductase in experimental acute renal-allograft rejection
Role of xanthine oxidoreductase in experimental acute renal-allograft rejection
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DOI：
10.1097/01.tp.0000131169.29553.b1
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发表时间：
2004-06-15
期刊：
影响因子：
6.2
通讯作者：
Gröne, HJ
中科院分区：
文献类型：
--
作者：
Sun, K;Kiss, E;Gröne, HJ
背景氧自由基的产生增加不仅可能导致移植后缺血再灌注损伤，而且可能导致移植肾的急性排斥反应。黄嘌呤氧化还原酶（XOR）可能构成相关的活性氧（ROS）来源。本研究的目的是（1）确定肾移植物中ROS的产生以及氧化剂和抗氧化酶的活性;（2）通过给予一种特异性XOR抑制剂钨来调节急性排斥反应。在使用或不使用钨的情况下进行了同系移植肾（刘易斯至刘易斯，Fisher 344至Fisher 344）和同种异体移植肾（Fisher 344至刘易斯）移植。在移植后第1、3或9天进行分析。ROS的产生增强，在第9天，肾移植物中的ROS比对照肾高10倍（P < 0.01）;这与急性排斥反应的组织学体征有关。氧自由基产生的显着程度增强XOR活性，增加了10倍以上，在移植后第9天的肾移植; XOR蛋白在肾小球和肾小管移植物中也升高。此外，NADPH氧化酶活性在同种异体移植物中显著增加。抗氧化酶活性呈下降趋势。钨处理导致XOR活性和ROS产生的显着减少，对NADPH氧化酶活性没有任何影响;通过选择性抑制XOR，移植后第9天单核细胞浸润和排斥反应体征显着改善。在急性排斥反应中，ROS的产生主要由XOR贡献。ROS不仅与同种异体移植急性排斥反应有关，而且也参与其中，因为抑制XOR可减轻排斥反应现象。
Background. Increased oxygen radical production may not only contribute to posttransplant ischemia-reperfusion injury but also to acute rejection of renal allografts. Xanthine oxidoreductase (XOR) may constitute a relevant reactive oxygen species (ROS) source. The study was conducted (1) to determine ROS production as well as oxidant and antioxidant enzyme activities in renal grafts and (2) to modulate acute rejection by tungsten administration, a specific inhibitor of XOR.Methods. Syngraft (Lewis to Lewis, Fisher344 to Fisher344) and allograft (Fisher344 to Lewis) kidney transplantations were performed with or without tungsten administration. Analysis was performed at day 1, 3, or 9 posttransplantation.Results. Generation of ROS was enhanced, being 10-fold higher in renal allografts versus control kidneys at day 9 (P < 0.01); this was associated with histologic signs of acute rejection. Oxygen radicals were generated to a significant degree by enhanced XOR activity, which increased more than 10-fold in renal allografts at day 9 posttransplantation; XOR protein in glomeruli and tubulointerstitium was also elevated in allografts. In addition, NADPH oxidase activity increased significantly in allografts. The activity of antioxidant enzymes tended to decrease. Tungsten treatment resulted in a pronounced reduction of XOR activity and ROS production, without any effect on NADPH-oxidase activity; mononuclear cell infiltration and rejection signs were significantly ameliorated at day 9 posttransplantation by selective inhibition of XOR.Conclusions. A major part of ROS generation in acute rejection was contributed by XOR. ROS are not only associated with but also contribute to acute allograft rejection because inhibition of XOR alleviated rejection phenomena.