Protective effects of a carbon monoxide-releasing molecule (CORM-3) during hepatic cold preservation |
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| Authors: | MD Pizarro JV Rodriguez ME Mamprin BJ Fuller BE Mann R Motterlini EE Guibert |
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| Institution: | 1. Farmacología, Departamento de Ciencias Fisiológicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, UNESCO Chair in Cryobiology, Suipacha 570 (S2002LRK), Rosario, Argentina;2. University Department of Surgery and Liver Transplant Unit, Royal Free & UCL Medical School, UCL, Hampstead Campus, UNESCO Chair in Cryobiology, London NW3 2QG, United Kingdom;3. Department of Chemistry, University of Sheffield, United Kingdom;4. Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, United Kingdom;5. Department of Drug Discovery and Development, Italian Institute of Technology, Genova, Italy;6. Biología Molecular, Departamento Ciencias Biológicas, Fac. de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, UNESCO Chair in Cryobiology, Suipacha 570 (S2002LRK), Rosario, Argentina |
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| Abstract: | 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 μM 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.ConclusionsThese 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. |
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| Keywords: | Carbon monoxide-releasing molecules UW solution Liver function Isolated perfused liver |
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