Protection Against Ischemia/Reperfusion Injury in Cardiac and Renal Transplantation with Carbon Monoxide, Biliverdin and Both

Abstract

Both carbon monoxide (CO) and biliverdin, products of heme degradation by heme oxygenase, have been shown to attenuate ischemia/reperfusion (I/R) injury. We hypothesized in this study that dual-treatment with CO and biliverdin would induce enhanced protective effects against cold I/R injury. Heterotopic heart and orthotopic kidney transplantation were performed in syngeneic Lewis rats after 24-h cold preservation in UW solution. While monotherapy with CO (20 ppm) or biliverdin (50 mg/kg, ip) did not alter the survival of heart grafts, dual-treatment increased survival to 80% from 0% in untreated recipients, with a significant decrease of myocardial injury and improved cardiac function. Similarly, dual-treatment significantly improved glomerular filtration rates of renal grafts and prolonged recipient survival compared to untreated controls. I/R injury-induced up-regulation of pro-inflammatory mediators (e.g. TNF-a , iNOS) and extravasation of inflammatory infiltrates were significantly less with dual-treatment than untreated controls. In addition, dual-treatment was effective in decreasing lipid peroxidation and improving graft blood flow through the distinctive action of biliverdin and CO, respectively. The study shows that the addition of byproducts of heme degradation with different mechanisms of action provides enhanced protection against transplant-associated cold I/R injury of heart and kidney grafts.

Heme Oxygenase-2 Is a Critical Determinant for Execution of an Acute Inflammatory and Reparative Response

“…Sustained increases in their levels have been associated with persistent inflammation, neovascularization, and decreased re-epithelialization and tissue repair. 44 -47 The fact that these same chemokines are subjected to down-regulation by either HO-1 induction or supplementation of CO or biliverdin, 21,43,48,49 further underscores the notion that the absence of considerable HO activity promoted the uncontrolled massive production of proinflammatory signals and, consequently, chronic inflammation and neovascularization. This is strongly supported by the demonstration that biliverdin administration rescued the impaired inflammatory and reparative response of the HO-2-null mice; it accelerated wound repair, promoted resolution, and attenuated neovascularization.…”

Curcumin reduces cold storage-induced damage in human cardiac myoblasts

“…This last aspect is of special interest for transplantation procedures as organs are usually kept at 4 o C in storage solutions before the actual transplant surgery. HO-1 and its products biliverdin, bilirubin and carbon monoxide exert beneficial effects that include protection against ischemia-reperfusion damage (Clark et al, 2000bForesti et al, 2001;Sandouka et al, 2006), mitigation of oxidative and nitrosative stress Kaur et al, 2003;Taille et al, 2005) and prolongation of graft survival of liver, heart and kidney allografts in experimental animal models of transplantation (Soares et al, 2001;Clark et al, 2003;Motterlini et al, 2005;Nakao et al, 2005). Because of its antioxidant and anti-inflammatory characteristics, the HO-1 pathway is potentially an excellent candidate to be exploited for amelioration of organ transplantation outcomes and survival Curcumin reduces cold storage-induced damage in human cardiac myoblasts Sandouka et al, 2006).…”

Biliverdin inhibits activation of NF‐κB: Reversal of inhibition by human biliverdin reductase

“…[9][10][11][12][13][14][15][16][17] Oxidative stress has been linked to the etiology of a wide spectrum of pathophysiological conditions, including cancer, neurological disorders and inflammatory diseases. [18][19][20][21][22] The contribution of hBVR to antioxidant protection offered by induction of the stress-inducible ho-1 was demonstrated by the observation that inhibition of hBVR, by siRNA treatment potentiates ROS-mediated damage to cells and promotes apoptosis. 23 BVR is known as a biliverdin-converting enzyme; however, recent findings have uncovered additional functions of the human reductase that relate to its kinase activity and reflect its structural features.…”