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.

Protective Effect of Carbon Monoxide–Releasing Compounds in Ischemia-Induced Acute Renal Failure

“…There have been several reports that inhalation of CO can be protective against acute rejection of intestine, lung, and kidney transplants (11,12,23,24). The protective actions of CO inhalation in transplantation are associated with a decrease in inflammation and apoptosis.…”

“…The anti-inflammatory actions of CO inhalation are associated with a decrease in cytokines such as IL-6 and inducible nitric oxide synthase as well as an increase in the total antioxidant power (11). Because analogous mechanisms are believed to contribute to tissue injury after renal ischemia, it is possible that the CO released from transition metal carbonyls is able to Figure 6.…”

“…One approach has been to use direct CO inhalation therapy at concentrations that increase carboxyhemoglobin levels to 25% after CO inhalation. Recent studies have indicated that CO inhalation therapy is able to protect both intestinal and renal grafts from ischemic damage in experimental models (11,12). However, CO inhalation therapy does have the potential to induce clinical toxicity to achieve the systemic carboxyhemoglobin levels required for therapeutic benefits.…”

Histidine-Tryptophan-Ketoglutarate or Celsior: Which Is More Suitable for Cold Preservation for Cardiac Grafts From Older Donors?

“…Western blots were performed using anti-adenosine monophosphate-activated protein kinase (AMPK)-alpha rabbit monoclonal antibodies, anti-phosphorylated (pThr 172) AMPK-alpha (Cell Signaling, Boston, MA), rabbit monoclonal antibodies for anti-cleaved caspase-3 (Cell Signaling,) and mouse anti-human monclonal antibody for human ␤-actin (Sigma) [21].…”

Pyrrolidine dithiocarbamate reduces ischemia-reperfusion injury of the small intestine

“…Hence, tissue viability increases because of improved nutritional supply and better elimination of toxic residues of oxidative stress. Recently, Nakao et al [30] demonstrated that inhalation of CO ameliorates IR injury in a model of bowel transplantation.…”