Carbon monoxide (CO), a product of heme metabolism by heme oxygenases, is known to impart protection against oxidative stress. We hypothesized that CO would protect ischemia-reperfusion (I/R) injury of transplanted organs, and the efficacy of CO was studied in the rat kidney transplantation model. A Lewis rat kidney graft, preserved in University of Wisconsin solution at 4 degrees C for 24 h, was orthotopically transplanted into syngeneic rats. Recipients were maintained in room air or exposed to CO (250 ppm) in air for 1 h before and 24 h after transplantation. Animals were killed 1, 3, 6, and 24 h after transplantation to assess efficacy of inhaled CO. Rapid upregulation of mRNA for IL-6, IL-1beta, TNF-alpha, ICAM-1, heme oxygenase-1, and inducible nitric oxide synthase was observed within 3 h after transplantation in the control grafts of air-exposed recipients, associating with histopathological evidences of acute tubular necrosis, interstitial hemorrhage, and edema. In contrast, the increase of inflammatory mediators was markedly inhibited in kidney grafts of CO-treated recipients, which correlated with improved renal cortical blood flow. Further detailed morphological analyses revealed that CO preserved the glomerular vascular architecture and podocyte viability with less apoptosis of tubular epithelial cells and less ED1(+) macrophage infiltration. CO inhalation resulted in improved serum creatinine levels and clearance, and animal survival was significantly improved with CO to 60.5 from 25 days in untreated controls. The study demonstrates that exposure of kidney graft recipients to CO at a low concentration can impart significant protective effects against renal I/R injury and improve function of renal grafts.