Heme oxygenase-1 system in organ transplantation1

Abstract

The heme oxygenase-1 (HO-1) system, the rate-limiting step in the conversion of heme, is among the most critical of cytoprotective mechanisms activated during cellular stress. The cytoprotection may result from the elimination of heme and the function of HO-1 downstream mediators, that is, biliverdin, carbon monoxide, and free iron. HO-1 overexpression exerts beneficial effects in a number of transplantation models, including antigen-independent ischemia/reperfusion injury, acute and chronic allograft rejection, and xenotransplantation. The HO-1 system is thought to exert four major functions: (1) antioxidant function; (2) maintenance of microcirculation; (3) modulatory function upon the cell cycle; and (4) anti-inflammatory function. The antioxidant function depends on heme degradation, oxygen consumption, biliverdin, and production of ferritin via iron accumulation. The production of carbon monoxide, which has vasodilation and antiplatelet aggregation properties, maintains tissue microcirculation and may be instrumental in antiapoptotic and cell arrest mechanisms. Heme catabolism and HO-1 overexpression exert profound direct and indirect inhibitory effects on the cascade of host inflammatory responses mediated by neutrophils, macrophages, and lymphocytes. These anti-inflammatory properties result in cytoprotection in a broad spectrum of graft injury experimental models, including ischemia/reperfusion, acute and chronic allograft, and xenotransplant rejection. Further, the multifaceted targets of HO-1-mediated cytoprotection may simultaneously benefit both local graft function and host systemic immune responses. Thus, the HO-1 system serves as a novel therapeutic concept in organ transplantation.

Cold ischemic injury of transplanted kidneys: new insights from experimental studies

“…We demonstrated that overexpression of HO-1 in renal tubular cells, either through gene transfer or induction with hemin, can protect these cells against cold storage injury (64). Our in vitro finding corroborates in vivo findings of others in heart, kidney, and liver transplantation models (30). HO-1 through the release of free iron stimulates synthesis of ferritin, the main cellular repository for free iron (64).…”

“…The finding that iron is released in copious amount in the cold (26) and that HO-1, which induces ferritin, protects cells against cold strongly suggests ferritin as an important mechanism for HO-1 protection. HO-1 also produces CO and bilirubin, both of which are suggested to contribute to the cytoprotective properties of HO-1 (5,30). In essence, there is a strong scientific basis and much experimental backing to put the HO-1 concept to the test in a clinical trial.…”

The utility of marginal donors in liver transplantation

“…109 Evidence suggests that overexpression of heme oxygenase-1 (HO-1), also known as hsp32, exerts potent cytoprotective effects. 110,111 HO-1 belongs to a family of enzymes involved in the catabolism of heme into bilirubin, free iron, and carbon monoxide (CO) (Fig. 3).…”

“…[110][111][112] HO-1 prevents the deleterious effects of heme, which promotes lipid peroxidation and free radical formation. 110 The mechanisms underlying HO-1's beneficial effects against IR injury have yet to be elucidated, but may be related to the production of CO. CO, released directly from heme, may act as a regulatory molecule in cellular and biologic processes, including endothelium vasodilatation, 113 inhibition of platelet aggregation, 114 suppression of inducible nitric oxide synthase, 112 down-regulation of procytokines via the mitogen-activated protein kinase pathways, 115 and inhibition of endothelial apoptosis. 116 Investigations in which HO-1 is up-regulated through pharmacologic induction (cobalt protophorphyrin) or gene therapy have shown promising results in attenuating IR injury and prolonging graft survival.…”

Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

“…HO-1 also possesses critical cytoprotective functions that are activated under cellular stress situations, such as inflammation, ischaemia, hypoxia, hyperoxia, hyperthermia or radiation [9]. HO-1 exerts major cytoprotective functions against inflammation, apoptosis and oxidative damage, and acts in the maintenance of microcirculation [10]. Accumulating evidence indicates that HO-1 plays an important role in immune regulation.…”