Ex vivo carbon monoxide prevents cytochrome P450 degradation and ischemia/reperfusion injury of kidney grafts

Abstract

Renal ischemia/reperfusion injury is a major complication of kidney transplantation. We tested if ex vivo delivery of carbon monoxide (CO) to the kidney would ameliorate the renal injury of cold storage that can complicate renal transplantation. Orthotopic syngeneic kidney transplantation was performed in Lewis rats following 24 h of cold preservation in University of Wisconsin solution equilibrated without or with CO (soluble CO levels about 40 microM). Ischemia/reperfusion injury in control grafts resulted in an early upregulation of inflammatory mediator mRNAs and progressive deterioration of graft function. In contrast, the grafts preserved with CO had significantly less oxidative injury and this was associated with improved recipient survival compared to the control group. Renal injury in the control group showed considerable degradation of cytochrome P450 heme proteins, active heme metabolism and increased detrimental intracellular free heme levels. Kidney grafts preserved in CO-equilibrated solution maintained their cytochrome P450 protein levels, had normal intracellular heme levels and had less lipid peroxidation. Our results show that CO-mediated suppression of injurious heme-derived redox reactions offers protection of kidney grafts from cold ischemia/reperfusion injury.

High-pressure carbon monoxide preserves rat kidney grafts from apoptosis and inflammation

“…Nakao and colleagues also demonstrated that lowconcentration CO inhalation provided protection against cold I/R injury in a rat kidney transplantation model. 17 Similar protective results can be achieved after storage of grafts in a UW solution saturated with CO. 18,19 Sener et al 20 demonstrated that carbon monoxide releasing molecules (CORM) supplementation in UW solution has a significant impact on decreasing cellular and graft injury, and improving rat kidney graft survival through its anti-apoptotic effects. Recently, Ruan Y et al 21 reported the protective effect of CO from CORM on renal ischemia-reperfusion injury is associated with the inhibition of high-mobility group box 1 (HMGB1) translocation and release.…”

Carbon Monoxide–Bound Red Blood Cells Protect Red Blood Cell Transfusion-Induced Hepatic Cytochrome P450 Impairment in Hemorrhagic-Shock Rats

“…Nakao et al, 2008 recently reported an interesting observation, in which the exposure of organ preservation solutions to CO was effective in suppressing the postreperfusion reduction in renal P450 levels in a rat model of kidney transplantation. This suggests that the use of CO might be useful in reducing P450 levels, even in the case of resuscitation from hemorrhagic shock via an RBC transfusion.…”

Impact of environmental factors on alloimmunity and transplant fate

“…However, CO at low concentrations was found to have cytoprotective effects through binding of iron-containing enzymes such as cytochrome P450. Using CO-containing preservation solution, Nakao et al demonstrated reduced inflammation and increased graft survival in treated kidneys prior to transplant surgery (103). Similar protection was observed with incubation of lung and intestinal transplants with low concentrations of CO (5%) and was associated with reduced intragraft inflammation following ischemia/reperfusion injury (IRI) (104,105).…”