Carbon monoxide-foe or friend?

ISCHEMIA-reperfusion injury (IRI) describes a pathological process that occurs after the restoration of blood flow to an ischemic organ. IRI can affect virtually any organ or organ system and, as a result, cause a wide range of clinical sequelae. By its nature solid organ transplantation cannot take place without IRI to the transplanted organ. In renal transplantation the clinical manifestations of IRI are diverse, ranging from barely noticeable in living donor transplantation to the leading contributor to delayed graft function in deceased donor renal transplantation. With extended criteria donor kidney transplantation, slightly more than 30% of patients will require dialysis within posttransplantation week 1. 1 Thus, due to a prolonged hospital stay, increased risk of rejection and increased cost, it becomes evident that mitigating IRI can have a significant impact on decreasing complications and costs, even potentially increasing the number of transplantable organs. Diverse pharmacological approaches to reduce IRI have been pursued in the last 3 decades. One of the first clinical strategies used superoxide dismutase to scavenge free radicals, which at that time were considered to be primary mediators of IRI mediated cellular damage. Through these early and subsequent experiments, investigators gained greater understanding of the molecular processes involved in IRI. Currently, it is believed that IRI involves cellular and molecular changes that lead to capillary leakage, immune activation, alterations in microvascular tone, reprogramming of cellular transcripts and cell death programs. This increased understanding has enlarged the target of therapeutic approaches. Today ongoing preclinical and early phase clinical trials are examining apoptosis inhibitors, immune suppressants, toll-like receptor inhibitors, angiogenesis promoters and a host of other small molecules. In this issue of The Journal Sener et al (page 772) present a novel approach to ameliorating IRI using the carbon monoxide releasing molecule (CORM), CORM-3. 2 CORMs are compounds that contain a heavy metal such as nickel, cobalt or iron, which surround a carbonyl group. Certain metal complexes can promote carbonyl dissociation, which in turn can bring about direct biological activities. 3 Initial in vitro studies showed a vasodilatory effect of CORMs and an antihypertensive effect in vivo. In the current series the effect of CORM-3 on recovery from IRI was studied in in vitro and in vivo models. In the in vitro model supplementation of cell culture with CORM-3 led to a clear and marked reduction in apoptosis and membrane damage. Furthermore, in a prolonged cold ischemia (26 hours) model of rat renal isotransplantation administering CORM during organ perfusion and before reperfusion led to significant prolongation of graft survival, improved graft function, and decreased glomerular and tubular necrosis. Moreover, CORM-3 could be administered at relatively late time points (immediately before reperfusion) and still provide a beneficial effect. The science behind IRI is growing rapidly. Advances in pharmacological approaches similar to these as well as mechanical approaches, such as ex vivo, warm oxygenated perfusion systems, are promising strategies to minimize the burden of IRI.