Protective effect of carbon monoxide in transplantation

Abstract

During the last decades due to the development of new immunosuppressive agents and improvements in organ preservation methods, surgical techniques, and postoperative care, organ transplantation has become an ultimate therapeutic option for irreversible organ failure. Early graft survival has significantly improved; however, the long-term outcome remains unsatisfactory. Multiple factors, both immunogenic and non-immunogenic etiologies, are involved in the deterioration of the allografts, and the recent use of expanded criteria donors to overcome the organ shortage may also contribute to the graft losses. Carbon monoxide (CO) is commonly viewed as a poison in high concentrations due to its ability to interfere with oxygen delivery. However, CO is endogenously produced in the body as a byproduct of heme degradation by the heme oxygenase (HO) and has recently received notable attention as a gaseous regulatory molecule. In fact, an augmentation of endogenous CO by induction of HO-1 or exogenously added CO is known to have potent cytoprotective effects in various disease models. Several recent reports have demonstrated that CO provides potent cytoprotective effects in the field of organ and cell transplantation. CO is able to prevent ischemia/reperfusion injury, allograft rejection, and xenograft rejection via its anti-inflammatory, anti-apoptotic and anti-proliferation effects, suggesting that CO might be a valuable therapeutic option in the field of transplantation. Based on the recent advancement of our understanding of CO as a new therapeutic molecule, this review attempts to summarize the functional roles as well as biological and molecular mechanisms of CO in transplantation and discusses potential CO application to the clinical transplant setting.

Key Features of the Intragraft Microenvironment that Determine Long-Term Survival Following Transplantation

“…Thus, the initial loss of microvessels/peritubular capillaries may be a primary factor in the development of fibrosis and chronic renal disease (Kang et al, 2002; Reinders and Briscoe, 2002; Contreras and Briscoe, 2007; Mayer, 2011). Pharmacologic therapy which can protect microvascular integrity at early times post transplantation has potential to improve long-term graft survival (Johnson et al, 2006; Nakao et al, 2006; Aydin et al, 2007; Rabelink et al, 2007; Briscoe and Pal, 2008; Leonard et al, 2008; Hanto et al, 2010). If early protection and repair is not accomplished, then ongoing local ischemia will result in cellular atrophy, and chronic allograft disease will be inevitable.…”

Gene Transfer of Inducible Nitric Oxide Synthase Affords Cardioprotection by Upregulating Heme Oxygenase-1 Via a Nuclear Factor-κB-Dependent Pathway

“…Of the metabolites generated by HO-1 catalysis, biliverdin (and bilirubin) has been shown to possess antioxidant activity, while carbon monoxide has been found to exert many salutary effects in various settings including myocardial ischemia 7, 11, 12. Although induction of HO-1 is known to constitute a common adaptive response that increases cellular resistance to oxidative injury and other types of injury 7, 12, 13, the role of HO-1 in the cardioprotection afforded by iNOS gene therapy remains unclear.…”

Preservation of the kidney by carbon monoxide: a black swan phenomenon

“…This salutary property of CO was shown in 1999 in a landmark study that demonstrated that CO, at relatively low concentrations (50–500 parts per million), protected against hyperoxia-induced lung injury by suppressing inflammation and apoptosis 6. These findings presaged a groundswell of investigations demonstrating the beneficial effects of CO (when present in such low concentrations) in diverse models of tissue injury, and which reflected, depending on the disease model, any one or combination of the following properties of CO: antiapoptotic, anti-inflammatory, immune-suppressant, antithrombotic, angiogenic, antifibrotic, and vasorelaxant 2–4,7,8. Moreover, such protection was conferred not only by CO administered as a gas but also by novel CO-releasing compounds 3…”

“…The cytoprotective properties of HO-1 were rapidly explored in the field of transplantation and were observed to mitigate ischemia/reperfusion injury of the transplanted kidney, acute renal allograft rejection, and chronic allograft nephropathy; these protective effects were recapitulated, in part, by products of HO such as CO and/or bile pigments 7,8. Attention was also directed to organ preservation, an issue of central importance in this field, and one renewed by the increasing use of marginal donor organs.…”

“…An intriguing question is whether low-grade oxidant generation in the donor kidney, induced by CO during cold storage, may condition the kidney so as to render the organ resistant to the surge of oxidative stress expected during the phase of reoxygenation/reperfusion. Irrespective of the mechanism underlying the beneficial effects of CO, the significance of the study of Nakao et al 1 is that it provides a CO-based strategy for kidney preservation, one that is applicable to other organs,7 and one that may also be proffered by CO-releasing molecules 3…”