Anti-thrombin therapy during warm ischemia and cold preservation prevents chronic kidney graft fibrosis in a DCD model.
Anti-thrombin therapy during warm ischemia and cold preservation prevents chronic kidney graft fibrosis in a DCD model.
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DOI：
10.1111/j.1600-6143.2009.02924.x
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Hauet T
中科院分区：
文献类型：
--
作者：
Favreau F;Thuillier R;Cau J;Milin S;Manguy E;Mauco G;Zhu X;Lerman LO;Hauet T
缺血再灌注损伤（IRI）通过肾小管周围毛细血管损伤对肾纤维化的发展至关重要。凝血是这一过程中的一个关键机制。在一个自体移植肾模型中，使用大白猪对美拉加群®（M）——一种凝血酶抑制剂进行了评估。为了模拟心脏死亡后的供体条件，肾脏在威斯康星大学溶液中冷保存24小时之前经历60分钟的热缺血（WI）。在热缺血之前和/或在保存液中使用M治疗，显著提高了3个月时的存活率，减少了与通过天狼星红染色检测到的间质纤维化严重减少相关的肾功能障碍。组织分析显示，M治疗后转化生长因子 - β（TGF - β）的表达及其效应物磷酸化 - Smad3、Smad4和结缔组织生长因子（CTGF）的激活水平降低。还观察到纤维蛋白溶解激活，表现为PAI - 1蛋白和基因表达下调。此外，M降低了S100A4表达和波形蛋白染色，它们是上皮 - 间质转化的标志物，而上皮 - 间质转化是慢性肾纤维化的一个主要途径。最后，氧化应激标志物Nox2和iNOS的表达降低。我们得出结论，凝血酶抑制是一种针对IRI的有效疗法，可减少慢性移植物纤维化，对存活率有显著的积极影响。
Ischemia reperfusion injury (IRI) is pivotal for renal fibrosis development via peritubular capillaries injury. Coagulation represents a key mechanism involved in this process. Melagatran® (M), a thrombin inhibitor, was evaluated in an autotransplanted kidney model, using Large White pigs. To mimic deceased after cardiac death donor conditions, kidneys underwent warm ischemia (WI) for 60 min before cold preservation for 24 hours in University of Wisconsin solution. Treatment with M before WI and/or in the preservation solution drastically improved survival at 3 months, reduced renal dysfunction related to a critical reduction in interstitial fibrosis, measured by Sirius Red staining. Tissue analysis revealed reduced expression of transforming growth factor-β (TGF-β) and activation level of its effectors phospho-Smad3, Smad 4 and connective tissue growth factor (CTGF) after M treatment. Fibrinolysis activation was also observed, evidenced by downregulation of PAI-1 protein and gene expression. In addition, M reduced S100A4 expression and vimentin staining, which are markers for epithelial mesenchymal transition, a major pathway to chronic kidney fibrosis. Finally, expression of oxidative stress markers Nox2 and iNOS was reduced. We conclude that inhibition of thrombin is an effective therapy against IRI which reduces chronic graft fibrosis, with a significantly positive effect on survival.
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