Pizarro M D, Rodriguez J V, Mamprin M E, Fuller B J, Mann B E, Motterlini R, Guibert E E
Departamento de Ciencias Fisiológicas, Universidad Nacional de Rosario, Argentina.
Cryobiology. 2009 Jun;58(3):248-55. doi: 10.1016/j.cryobiol.2009.01.002.
There is increasing evidence that carbon monoxide (CO), a signaling molecule generated during the degradation of heme by heme oxygenase-1 (HO-1) in biological systems, has a variety of cytoprotective actions, including anti-hypoxic effects at low temperatures. However, during liver cold preservation, a direct effect needs to be established. Here, we designed a study to analyze the role of CO, delivered via a carbon monoxide-releasing molecule (CO-RM) in the maintenance of liver function, and integrity in rats during cold ischemia/reperfusion (CI/R) injury. We used an isolated normothermic perfused liver system (INPL) following a clinically relevant model of ex vivo 48 h cold ischemia stored in a modified University of Wisconsin (UW) solution, to determine the specific effects of CO in a rat model. CO was generated from 50 microM tricarbonylchloro ruthenium-glycinato (CORM-3), a water-soluble transition metal carbonyl that exerts pharmacological activities via the liberation of controlled amounts of CO in biological systems. The physiological effects of CORM-3 were confirmed by the parallel use of a specific inactive compound (iCORM-3), which does not liberate CO in the cellular environment. CORM-3 addition was found to prevent the injury caused by cold storage by improving significantly the perfusion flow during reperfusion (by almost 90%), and by decreasing the intrahepatic resistance (by 88%) when compared with livers cold preserved in UW alone. Also, CORM-3 supplementation preserved good metabolic capacity as indicated by hepatic oxygen consumption, glycogen content, and release of lactate dehydrogenase. Liver histology was also partially preserved by CORM-3 treatment.
These findings suggest that CO-RM could be utilized as adjuvant therapeutics in UW solutions to limit the injury sustained by donor livers during cold storage prior to transplantation, as has been similarly proposed for the heart, and kidney.
越来越多的证据表明，一氧化碳（CO）作为生物系统中血红素加氧酶 -1（HO -1）降解血红素过程中产生的一种信号分子，具有多种细胞保护作用，包括在低温下的抗缺氧作用。然而，在肝脏冷保存过程中，其直接作用尚需确定。在此，我们设计了一项研究，以分析通过一氧化碳释放分子（CO -RM）递送的CO在大鼠冷缺血/再灌注（CI/R）损伤期间对肝功能维持及肝脏完整性的作用。我们采用了一种分离的常温灌注肝脏系统（INPL），该系统遵循一种临床相关的体外48小时冷缺血模型，肝脏保存在改良的威斯康星大学（UW）溶液中，以确定CO在大鼠模型中的具体作用。CO由50微摩尔的三羰基氯钌 -甘氨酸（CORM -3）产生，CORM -3是一种水溶性过渡金属羰基化合物，通过在生物系统中释放可控量的CO发挥药理活性。通过同时使用一种在细胞环境中不释放CO的特定无活性化合物（iCORM -3），证实了CORM -3的生理效应。与仅保存在UW溶液中的冷保存肝脏相比，发现添加CORM -3可通过显著改善再灌注期间的灌注流量（近90%）以及降低肝内阻力（88%）来预防冷保存引起的损伤。此外，补充CORM -3可保持良好的代谢能力，如肝脏耗氧量、糖原含量以及乳酸脱氢酶的释放所示。CORM -3处理还部分保留了肝脏组织学结构。
这些发现表明，CO -RM可作为UW溶液中的辅助治疗药物，以限制移植前供体肝脏在冷保存期间所遭受的损伤，心脏和肾脏也曾有过类似的提议。
