Matthew Mailing Centre for Translational Transplantation Studies, Western University, London, Canada.
Multi Organ Transplant Program, Western University, London, Canada.
Transplantation. 2018 Jul;102(7):1066-1074. doi: 10.1097/TP.0000000000002201.
Carbon monoxide (CO) inhalation protects organ by reducing inflammation and cell death during transplantation processes in animal model. However, using CO in clinical transplantation is difficult due to its delivery in a controlled manner. A manganese-containing CO releasing molecules (CORM)-401 has recently been synthesized which can efficiently deliver 3 molar equivalents of CO. We report the ability of this anti-inflammatory CORM-401 to reduce ischemia reperfusion injury associated with prolonged cold storage of renal allografts obtained from donation after circulatory death in a porcine model of transplantation.
To stimulate donation after circulatory death condition, kidneys from large male Landrace pig were retrieved after 1 hour warm ischemia in situ by cross-clamping the renal pedicle. Procured kidneys, after a brief flushing with histidine-tryptophan-ketoglutarate solution were subjected to pulsatile perfusion at 4°C with University of Wisconsin solution for 4 hours and both kidneys were treated with either 200 μM CORM-401 or inactive CORM-401, respectively. Kidneys were then reperfused with normothermic isogeneic porcine blood through oxygenated pulsatile perfusion for 10 hours. Urine was collected, vascular flow was assessed during reperfusion and histopathology was assessed after 10 hours of reperfusion.
We have found that CORM-401 administration reduced urinary protein excretion, attenuated kidney damage markers (kidney damage marker-1 and neutrophil gelatinase-associated lipocalin), and reduced ATN and dUTP nick end labeling staining in histopathologic sections. CORM-401 also prevented intrarenal hemorrhage and vascular clotting during reperfusion. Mechanistically, CORM-401 appeared to exert anti-inflammatory actions by suppressing Toll-like receptors 2, 4, and 6.
Carbon monoxide releasing molecules-401 provides renal protection after cold storage of kidneys and provides a novel clinically relevant ex vivo organ preservation strategy.
一氧化碳（CO）吸入通过减少动物模型移植过程中的炎症和细胞死亡来保护器官。然而，由于其以受控方式输送，因此在临床移植中使用 CO 较为困难。最近合成了一种含锰的 CO 释放分子（CORM）-401，它可以有效地输送 3 摩尔当量的 CO。我们报告了这种抗炎 CORM-401 减少与来自死后循环供体的肾移植的冷保存相关的缺血再灌注损伤的能力，在猪移植模型中。
为了刺激死后循环供体的条件，从原位肾蒂夹闭 1 小时后的大型雄性长白猪中获取肾脏。用组氨酸-色氨酸-酮戊二酸溶液短暂冲洗后，将采集的肾脏在 4°C 下用威斯康星大学溶液进行搏动性灌注 4 小时，然后分别用 200 μM CORM-401 或无活性 CORM-401 处理两个肾脏。然后用含氧的搏动性灌注使肾脏再灌注 10 小时的同基因猪血液。收集尿液，在再灌注期间评估血管流量，并在再灌注 10 小时后评估组织病理学。
我们发现 CORM-401 给药可减少尿蛋白排泄，减轻肾脏损伤标志物（肾脏损伤标志物-1 和中性粒细胞明胶酶相关脂质运载蛋白），并减少组织病理学切片中的 ATN 和 dUTP 尼克末端标记染色。CORM-401 还可防止再灌注期间肾内出血和血管内凝块形成。机制上，CORM-401 似乎通过抑制 Toll 样受体 2、4 和 6 发挥抗炎作用。
一氧化碳释放分子-401 可在肾脏冷保存后提供肾脏保护，并提供一种新的临床相关的离体器官保存策略。
