title: Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury.
abstract: Carbon monoxide (CO), a byproduct of heme catalysis by heme oxygenases, has been shown to exert anti-inflammatory effects. This study examines the cytoprotective efficacy of inhaled CO during intestinal cold ischemia/reperfusion injury associated with small intestinal transplantation. Orthotopic syngenic intestinal transplantation was performed in Lewis rats after 6 hours of cold preservation in University of Wisconsin solution. Three groups were examined: normal untreated controls, control intestinal transplant recipients kept in room air, and recipients exposed to CO (250 ppm) for 1 hour before and 24 hours after surgery. In air grafts, mRNA levels for interleukin-6, cyclooxygenase-2, intracellular adhesion molecule (ICAM-1), and inducible nitric oxide synthase rapidly increased after intestinal transplant. Histopathological analysis revealed severe mucosal erosion, villous congestion, and inflammatory infiltrates. CO effectively blocked an early up-regulation of these mediators, showed less severe histopathological changes, and resulted in significantly improved animal survival of 92% from 58% in air-treated controls. CO also significantly reduced mRNA for proapoptotic Bax, while it up-regulated anti-apoptotic Bcl-2. These changes in CO-treated grafts correlated with well-preserved CD31(+) vascular endothelial cells, less frequent apoptosis/necrosis in intestinal epithelial and capillary endothelial cells, and improved graft tissue blood circulation. Protective effects of CO in this study were mediated via soluble guanylyl cyclase, because 1H-(1,2,4)oxadiazole (4,3-alpha) quinoxaline-1-one (soluble guanylyl cyclase inhibitor) completely reversed the beneficial effect conferred by CO. Perioperative CO inhalation at a low concentration resulted in protection against ischemia/reperfusion injury to intestinal grafts with prolonged cold preservation.
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001808:Blood Vessels / Q000473:pathology / Q000648:ultrastructure; D002248:Carbon Monoxide / Q000008:administration & dosage*; D002263:Carboxyhemoglobin / Q000032:analysis; D016319:Corrosion Casting; D016207:Cytokines / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005740:Gases / Q000097:blood; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D018836:Inflammation Mediators / Q000378:metabolism; D007421:Intestine, Small / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D007511:Ischemia / Q000517:prevention & control*; D008297:Male; D009994:Osmolar Concentration; D010069:Oxadiazoles / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012039:Regional Blood Flow; D015427:Reperfusion Injury / Q000517:prevention & control*; D016019:Survival Analysis
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D016207:Cytokines; D004791:Enzyme Inhibitors; D005740:Gases; D018836:Inflammation Mediators; D010069:Oxadiazoles; D017395:Plasminogen Activator Inhibitor 1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011810:Quinoxalines; D012333:RNA, Messenger; D002248:Carbon Monoxide; D002263:Carboxyhemoglobin; D006162:Guanylate Cyclase