Harvard Medical School, the Transplant Institute and the Department of Surgery, Division of Transplantation at Beth Israel Deaconess Medical Center, Boston, MA, USA.
Am J Transplant. 2010 Nov;10(11):2421-30. doi: 10.1111/j.1600-6143.2010.03289.x.
Ischemia/reperfusion injury and delayed graft function (DGF) following organ transplantation adversely affect graft function and survival. A large animal model has not been characterized. We developed a pig kidney allograft model of DGF and evaluated the cytoprotective effects of inhaled carbon monoxide (CO). We demonstrate that donor warm ischemia time is a critical determinant of DGF as evidenced by a transient (4-6 days) increase in serum creatinine and blood urea nitrogen following transplantation before returning to baseline. CO administered to recipients intraoperatively for 1 h restored kidney function more rapidly versus air-treated controls. CO reduced acute tubular necrosis, apoptosis, tissue factor expression and P-selectin expression and enhanced proliferative repair as measured by phosphorylation of retinol binding protein and histone H3. Gene microarray analyses with confirmatory PCR of biopsy specimens showed that CO blocked proinflammatory gene expression of MCP-1 and heat shock proteins. In vitro in pig renal epithelial cells, CO blocks anoxia-reoxygenation-induced cell death while promoting proliferation. This large animal model of DGF can be utilized for testing therapeutic strategies to reduce or prevent DGF in humans. The efficacy of CO on improving graft function posttransplant validates the model and offers a potentially important therapeutic strategy to improve transplant outcomes.
缺血/再灌注损伤和移植后延迟肾功能（DGF）会对移植物功能和存活率产生不利影响。目前尚未建立大动物模型。本研究建立了 DGF 猪肾移植模型，并评估了吸入一氧化碳（CO）的细胞保护作用。研究结果表明，供体热缺血时间是 DGF 的一个关键决定因素，这表现为移植后血清肌酐和血尿素氮短暂（4-6 天）升高，然后恢复到基线。与空气处理对照组相比，CO 用于术中 1 小时的受体可更快地恢复肾功能。CO 减少了急性肾小管坏死、细胞凋亡、组织因子表达和 P-选择素表达，并通过视黄醇结合蛋白和组蛋白 H3 的磷酸化增强了增殖修复。通过活检标本的确认性 PCR 进行基因微阵列分析显示，CO 阻断了单核细胞趋化蛋白 1 和热休克蛋白的促炎基因表达。在猪肾上皮细胞中，CO 阻断了缺氧再复氧诱导的细胞死亡，同时促进了增殖。该 DGF 大动物模型可用于测试减少或预防人类 DGF 的治疗策略。CO 改善移植后移植物功能的功效验证了该模型，并提供了一种潜在的重要治疗策略，以改善移植结果。
