Carbon monoxide-releasing molecules protect against ischemia–reperfusion injury during kidney transplantation
2011; Elsevier BV; Volume: 79; Issue: 10 Linguagem: Inglês
10.1038/ki.2010.542
ISSN1523-1755
AutoresYves Caumartin, Jancy Stephen, Jian Deng, Dameng Lian, Lan Zhu, Weihua Liu, Bertha García, Anthony M. Jevnikar, Hao Wang, Gediminas Cepinskas, Patrick Luke,
Tópico(s)Organ Transplantation Techniques and Outcomes
ResumoCarbon monoxide (CO) can provide beneficial antiapoptotic and anti-inflammatory effects in the context of ischemia–reperfusion injury (IRI). Here we tested the ability of pretreating the kidney donor with carbon monoxide-releasing molecules (CORM) to prevent IRI in a transplant model. Isogeneic Brown Norway donor rats were pretreated with CORM-2 18 h before kidney retrieval. The kidneys were then cold-preserved for 26 h and transplanted into Lewis rat recipients that had undergone bilateral nephrectomy. Allografts from Brown Norway to Lewis rats were also performed after 6 h of cold ischemic time with low-dose tacrolimus treatment. All recipients receiving CORM-2-treated isografts survived the transplant process and had near-normal serum creatinine levels, whereas all control animals died of uremia by the third post-operative day. This beneficial effect was also seen in isografted Lewis recipients receiving kidneys perfused with CORM-3, indicating that CORMs have direct effects on the kidney. Pretreatment of human umbilical vein endothelial cells in culture with CORM-2 for 1 h significantly reduced cytokine-induced nicotinamide adenine dinucleotide phosphate-dependent production of superoxide, activation of the inflammation-relevant transcription factor nuclear factor-κB, upregulated expression of E-selectin and intercellular adhesion molecule-1 adhesion proteins, and leukocyte adhesion to the endothelial cells. Thus, CORM-2-derived CO protects renal transplants from IRI by modulating inflammation. Carbon monoxide (CO) can provide beneficial antiapoptotic and anti-inflammatory effects in the context of ischemia–reperfusion injury (IRI). Here we tested the ability of pretreating the kidney donor with carbon monoxide-releasing molecules (CORM) to prevent IRI in a transplant model. Isogeneic Brown Norway donor rats were pretreated with CORM-2 18 h before kidney retrieval. The kidneys were then cold-preserved for 26 h and transplanted into Lewis rat recipients that had undergone bilateral nephrectomy. Allografts from Brown Norway to Lewis rats were also performed after 6 h of cold ischemic time with low-dose tacrolimus treatment. All recipients receiving CORM-2-treated isografts survived the transplant process and had near-normal serum creatinine levels, whereas all control animals died of uremia by the third post-operative day. This beneficial effect was also seen in isografted Lewis recipients receiving kidneys perfused with CORM-3, indicating that CORMs have direct effects on the kidney. Pretreatment of human umbilical vein endothelial cells in culture with CORM-2 for 1 h significantly reduced cytokine-induced nicotinamide adenine dinucleotide phosphate-dependent production of superoxide, activation of the inflammation-relevant transcription factor nuclear factor-κB, upregulated expression of E-selectin and intercellular adhesion molecule-1 adhesion proteins, and leukocyte adhesion to the endothelial cells. Thus, CORM-2-derived CO protects renal transplants from IRI by modulating inflammation. Kidney transplantation remains the best option for patients suffering from end-stage renal disease.1.Wolfe R.A. Ashby V.B. Milford E.L. et al.Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant.N Engl J Med. 1999; 341: 1725-1730Crossref PubMed Scopus (3982) Google Scholar Over the last two decades, dramatically improved short-term outcomes following kidney transplantation have occurred.2.Doyle A.M. Lechler R.I. Turka L.A. Organ transplantation: halfway through the first century.J Am Soc Nephrol. 2004; 15: 2965-2971Crossref PubMed Scopus (23) Google Scholar Nevertheless, long-term graft survival and allograft half-life has failed to improve substantially during this period of time.3.Meier-Kriesche H.U. Schold J.D. Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies?.Am J Transplant. 2004; 4: 1289-1295Crossref PubMed Scopus (531) Google Scholar, 4.Meier-Kriesche H.U. Schold J.D. Srinivas T.R. et al.Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era.Am J Transplant. 2004; 4: 378-383Crossref PubMed Scopus (981) Google Scholar, 5.Wolfe R.A. Merion R.M. Roys E.C. et al.Trends in organ donation and transplantation in the United States, 1998-2007.Am J Transplant. 2009; 9: 869-878Crossref PubMed Scopus (60) Google Scholar, 6.McCullough K.P. Keith D.S. Meyer K.H. et al.Kidney and pancreas transplantation in the United States, 1998-2007: access for patients with diabetes and end-stage renal disease.Am J Transplant. 2009; 9: 894-906Crossref PubMed Scopus (96) Google Scholar It is likely that the limited improvements in allograft survival are related with the ongoing damage incurred by ischemia–reperfusion injury (IRI) as a result of prolonged preservation and organ revascularization. IRI has been shown to result in irreversible organ damage and has been speculated to participate in the chronic development of interstitial fibrosis and tubular atrophy. Unfortunately, effective strategies to prevent interstitial fibrosis and tubular atrophy have yet to be identified. Evidence indicates that carbon monoxide (CO) can provide beneficial antiapoptotic and anti-inflammatory effects in the context of IRI.7.Nakao A. Choi A.M. Murase N. Protective effect of carbon monoxide in transplantation.J Cell Mol Med. 2006; 10: 650-671Crossref PubMed Scopus (110) Google Scholar During IRI, endogenous CO is generated from heme degradation through heme oxygenase-1 activity.8.Wu L. Wang R. Carbon monoxide: endogenous production, physiological functions, and pharmacological applications.Pharmacol Rev. 2005; 57: 585-630Crossref PubMed Scopus (738) This pathway has been identified as a natural powerful cytoprotective mechanism.9.Courtney A.E. Maxwell A.P. Heme oxygenase 1: does it have a role in renal cytoprotection?.Am J Kidney Dis. 2008; 51: 678-690Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar More recently, low-dose exogenous CO has been studied in numerous transplant models, including kidney10.Nakao A. Faleo G. Nalesnik M.A. et al.Low dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function.Am J Physiol Renal Physiol. 2009; 207: F19Crossref Scopus (29) Google Scholar, 11.Nakao A. Faleo G. Shimizu H. et al.Ex vivo carbon monoxide prevents cytochrome P450 degradation and ischemia/reperfusion injury of kidney grafts.Kidney Int. 2008; 74: 1009-1016Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 12.Faleo G. Neto J.S. Kohmoto J. et al.Carbon monoxide ameliorates renal cold ischemia-reperfusion injury with an upregulation of vascular endothelial growth factor by activation of hypoxia-inducible factor.Transplantation. 2008; 85: 1833-1840Crossref PubMed Scopus (66) Google Scholar, 13.Martins P.N. Reutzel-Selke A. Jurisch A. et al.Induction of carbon monoxide in donor animals prior to organ procurement reduces graft immunogenicity and inhibits chronic allograft dysfunction.Transplantation. 2006; 82: 938-944Crossref PubMed Scopus (38) Google Scholar, 14.Neto J.S. Nakao A. Kimizuka K. et al.Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide.Am J Physiol Renal Physiol. 2004; 287: F979-F989Crossref PubMed Scopus (180) Google Scholar liver,15.Tomiyama K. Ikeda A. Ueki S. et al.Inhibition of Kupffer cell-mediated early proinflammatory response with carbon monoxide in transplant-induced hepatic ischemia/reperfusion injury in rats.Hepatology. 2008; 48: 1608-1620Crossref PubMed Scopus (75) Google Scholar, 16.Kaizu T. Nakao A. Tsung A. et al.Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation.Surgery. 2005; 138: 229-235Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar intestine,17.Nakao A. Toyokawa H. Tsung A. et al.Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury.Am J Transplant. 2006; 6: 2243-2255Crossref PubMed Scopus (91) Google Scholar, 18.Nakao A. Kimizuka K. Stolz D.B. et al.Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury.Am J Pathol. 2003; 163: 1587Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar lung,19.Zhou H.C. Ding W.G. Cui X.G. et al.Carbon monoxide inhalation ameliorates conditions of lung grafts from rat brain death donors.Chin Med J (Engl). 2008; 121: 1411-1498PubMed Google Scholar, 20.Kohmoto J. Nakao A. Sugimoto R. et al.Carbon monoxide-saturated preservation solution protects lung grafts from ischemia-reperfusion injury.J Thorac Cardiovasc Surg. 2008; 136: 1067-1075Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 21.Kohmoto J. Nakao A. Stolz D.B. et al.Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway.Am J Transplant. 2007; 7: 2279-2290Crossref PubMed Scopus (97) Google Scholar, 22.Kohmoto J. Nakao A. Kaizu T. et al.Low-dose carbon monoxide inhalation prevents ischemia/reperfusion injury of transplanted rat lung grafts.Surgery. 2006; 140: 179-185Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar and heart,23.Nakao A. Toyokawa H. Abe M. et al.Heart allograft protection with low-dose carbon monoxide inhalation: effects on inflammatory mediators and alloreactive T-cell responses.Transplantation. 2006; 81: 220-230Crossref PubMed Scopus (67) Google Scholar with promising results. However, exogenous CO administration has been shown to increase carboxyhemoglobin (COHb), with the theoretical risk of impaired oxygen delivery to organs and tissues.16.Kaizu T. Nakao A. Tsung A. et al.Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation.Surgery. 2005; 138: 229-235Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 24.Nakao A. Kimizuka K. Stolz D.B. et al.Protective effect of carbon monoxide inhalation for cold-preserved small intestinal grafts.Surgery. 2003; 134: 285-292Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar To circumvent this problem, novel CO-releasing molecules (CORMs) have been created to deliver consistent amounts of CO to tissues without a significant impact on COHb levels. CORMs have been shown to counteract numerous inflammatory conditions such as sepsis25.Sun B. Sun Z. Jin Q. et al.CO-releasing molecules (CORM-2)-liberated CO attenuates leukocytes infiltration in the renal tissue of thermally injured mice.Int J Biol Sci. 2008; 4: 176-183Crossref PubMed Scopus (61) Google Scholar, 26.Liu D.M. Sun B.W. Sun Z.W. et al.Suppression of inflammatory cytokine production and oxidative stress by CO-releasing molecules-liberated CO in the small intestine of thermally-injured mice.Acta Pharmacol Sin. 2008; 29: 838-846Crossref PubMed Scopus (37) Google Scholar, 27.Sun B.W. Chen X. Chen Z.Y. et al.Molecular mechanism of inhibition of early pulmonary injury and inflammatory response by exogenous carbon monoxide: experiment with mice.Zhonghua Yi Xue Za Zhi. 2007; 87: 3148-3151PubMed Google Scholar, 28.Sun B.W. Jin Q. Sun Y. et al.Carbon liberated from CO-releasing molecules attenuates leukocyte infiltration in the small intestine of thermally injured mice.World J Gastroenterol. 2007; 13: 6183-6190Crossref PubMed Scopus (29) Google Scholar, 29.Cepinskas G. Katada K. Bihari A. et al.Carbon monoxide liberated from carbon monoxide-releasing molecule CORM-2 attenuates inflammation in the liver of septic mice.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G184-G191Crossref PubMed Scopus (118) Google Scholar and coronary ischemia.30.Musameh M.D. Green C.J. Mann B.E. et al.Improved myocardial function after cold storage with preservation solution supplemented with a carbon monoxide-releasing molecule (CORM-3).J Heart Lung Transplant. 2007; 26: 1192-1198Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 31.Stein A.B. Guo Y. Tan W. et al.Administration of a CO-releasing molecule induces late preconditioning against myocardial infarction.J Mol Cell Cardiol. 2005; 38: 127-134Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar A few publications have also reported interesting results in renal IRI32.Vera T. Henegar J.R. Drummond H.A. et al.Protective effect of carbon monoxide-releasing compounds in ischemia-induced acute renal failure.J Am Soc Nephrol. 2005; 16: 950-958Crossref PubMed Scopus (122) Google Scholar and transplantation models.33.Bagul A. Hosgood S.A. Kaushik M. et al.Carbon monoxide protects against ischemia-reperfusion injury in an experimental model of controlled nonheartbeating donor kidney.Transplantation. 2008; 85: 576-581Crossref PubMed Scopus (56) Google Scholar, 34.Pizarro M.D. Rodriguez J.V. Mamprin M.E. et al.Protective effects of a carbon monoxide-releasing molecule (CORM-3) during hepatic cold preservation.Cryobiology. 2009; 58: 248-255Crossref PubMed Scopus (52) Google Scholar, 35.Sandouka A. Fuller B.J. Mann B.E. et al.Treatment with CO-RMs during cold storage improves renal function at reperfusion.Kidney Int. 2006; 69: 239-247Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar Thus far, CORM has yet to have been used in in vivo kidney transplant studies. Therefore, we hypothesized that CORM would prevent inflammation in transplant-relevant models of cellular injury. Specifically, we hypothesized that CORM could protect the kidney against IRI in a kidney transplant model. Donor rats were pretreated with 8 mg/kg intraperitoneal (IP) CORM-2 18 h before procurement and transplanted into isogeneic Lewis rats. Control rat donors were pretreated with (a) saline, (b) dimethyl sulfoxide (DMSO; used to dissolve CORM), (c) iCORM (inactivated CORM), or (d) CORM-2 plus soluble guanylate cyclase (sGC) inhibitor, ODQ. As shown in Figure 1a, recipients receiving the CORM-2-treated grafts were the only ones to survive the transplant process. In parallel, preconditioning of donor animals with CORM-2 resulted in abrogation of IRI with respect to the decreased serum levels of creatinine. As shown in Figure 1b, serum creatinine levels in CORM-2-treated animals were significantly lower as compared with all other control groups (except untransplanted normal animals) on post-operative day 3. Interestingly, ODQ pretreatment before CORM-2 donor preconditioning abrogated the protective effect of CORM-2, indicating that activation of sGC is critical to the protective mechanism of CORM-2. The histological analysis (light microscopy) of the isografts demonstrated that CORM-2-treated kidneys had reduced damage versus all other groups on post-operative day 2 (Figure 1c). Assessment of damage using an IRI severity score derived by pathologists blinded to the treatment groups indicated that control kidneys (iCORM-2, CORM-2+ODQ, and DMSO treatment) sectioned on day 2 sustained severe acute tubular injury (grade 2–3 injury); however, CORM-2-treated animals sustained far less injury (grade 0–1; Figure 1d). No differences were seen regarding monocyte or neutrophil infiltration of the interstitium. Brown Norway rats were pretreated with 8 mg/kg IP CORM-2 18 h before procurement and transplanted into allogeneic Lewis rats after a 6-h cold ischemic time. A reduced ischemic time was used as the synergistic stresses of allotransplantation and 26 h ischemia prevented long-term survival in animals (data not shown). Without immunotherapy, animals died within 3 days from uremia (creatinine 780±150 μmol/l) using this transplant model. In our experiment, a low dose of tacrolimus (0.2 mg/kg intravenously) was given to allograft recipients post-operatively. Control allografted animals did not receive CORM-2 infusion. None of the control animals survived beyond 12 days (mean 11.0 days), and recipients had inferior graft function versus CORM-2-treated animals at 7 days. Excellent graft function was noted on day 70 in CORM-2-treated animals (creatinine 52±9 μmol/l). Accordingly, histological examination on day 10 showed lymphocytic infiltrate, glomerular congestion, and acute tubular necrosis in controls, whereas CORM-2-treated animals had completely normal histology on day 10 (Figure 2c). By day 70, CORM-2-treated animals demonstrated vascular lymphocytic infiltrates and glomerular atrophy, despite having excellent renal function (not shown). This indicates that CORM-2 preconditioning has profound effects on allogeneic transplantation associated with reduction of inflammation and damage. After procurement from Lewis rats, kidneys were perfused with 100 μmol/l CORM-3 in University of Wisconsin solution (UW) and stored for 26 h before transplantation into Lewis recipients. CORM-3 was used in these experiments as DMSO solvent for CORM-2 was found to be directly toxic to tubular epithelial cells and attenuated graft survival (data not shown). Control kidneys were perfused and stored in UW solution for 26 h. Figure 3a demonstrates that none of the control animals survived the transplant process, whereas dramatically improved survival was seen in the CORM-treated animals (P<0.05). Similarly, renal function on day 3 was superior in the CORM-treated group versus control (Figure 3b), as was the renal histology (Figure 3c). CORM-3 perfusion was associated with reduced tubular necrosis (grade 0 versus 2) and glomerular necrosis (grade 0 versus 2) compared with control. These data indicate that CORM directly affects transplanted tissues. It has been demonstrated that interventions/pathologies associated with the organ/tissue ischemia/reperfusion (organ transplantation) results in a marked increase in the levels of circulating proinflammatory cytokines (for example, tumor necrosis factor (TNF)-α and interferon-γ), which have a key role in activation (for example, reactive oxygen species (ROS) production) of vascular endothelium and subsequent upregulation of the proadhesive endothelial phenotype. This inevitably leads to the overwhelming inflammatory cell (for example, polymorphonuclear (PMN)) recruitment to the afflicted sites, resulting in organ/tissue oxidative/proteolytic damage and impaired function.36.Carden D.L. Granger D.N. Pathophysiology of ischaemia-reperfusion injury.J Pathol. 2000; 190: 255-266Crossref PubMed Scopus (1421) Google Scholar Therefore, in the next series of experiments, we assessed the effect of CORM-2 on intracellular ROS production, activation of inflammation-relevant transcription factor, nuclear factor (NF)-κB, expression of adhesion molecules E-selectin, and intercellular adhesion molecule (ICAM)-1 in cytokine-stimulated vascular endothelial cells. As a functional correlate, PMN adhesion to endothelial cells was also assessed. To assess the effects of CORM-2-derived CO in modulation of intracellular oxidative stress, human umbilical vein endothelial cells (HUVECs) were treated with CORM-2, DMSO, iCORM-2, or with sGC inhibitor, ODQ, before CORM-2 treatment. HUVECs were stimulated with TNF-α/interferon-γ mixture at equimolar concentrations, and the lucigenin assay was used to measure nicotinamide adenine dinucleotide phosphate (NADPH)-dependent production of O2−. As shown in Figure 4, stimulation of HUVEC with TNF-α/interferon-γ markedly increased NADPH-dependent production of O2−. The latter effect was effectively suppressed in CORM-2 (but not in iCORM-2)-pretreated cells. Treating HUVECs with CORM-2 or iCORM-2 in the absence of cytokine stimulation had no effect on ROS production. Interestingly, pretreating HUVECs with ODQ did not abolish CORM-2 effects, as seen in the in vivo experiments. These results suggest that in the system consisting with a single cell type (i.e. endothelial cells) the protective effects of CORM-2 with respect to cytokine-induced NADPH-dependent production of O2− are sGC-independent. It has been demonstrated that increased production of ROS leads to activation of inflammation-relevant transcription factor, NF-κB.37.Cepinskas G. Lush C.W. Kvietys P.R. Anoxia/reoxygenation induced tolerance with respect to polymorphonuclear leukocyte adhesion to cultured endothelialo cells. A nuclear factor-kappaB-mediated phenomenon.Circ Res. 1999; 84: 103-112Crossref PubMed Scopus (50) Google Scholar Therefore, in the next series of experiments we assessed the effects of CORM-2 pretreatment on modulation of NF-κB activation in TNF-α/INF-γ-stimulated HUVECs. As shown in Figure 5, stimulation of HUVECs with TNF-α/INF-γ resulted in an induction of NF-κB activation as assessed by degradation of NF-κB inhibitory protein, IκB (inhibitory protein κ-B). Pretreatment of HUVECs with CORM-2 was effective in preventing cytokine stimulation-induced IκB degradation. As in the previous experiments (see Figure 4), interfering with sGC activity by ODQ failed to prevent the protective effects of CORM-2. Regulation of the vascular proadhesive phenotype is tightly controlled by NF-κB.37.Cepinskas G. Lush C.W. Kvietys P.R. Anoxia/reoxygenation induced tolerance with respect to polymorphonuclear leukocyte adhesion to cultured endothelialo cells. A nuclear factor-kappaB-mediated phenomenon.Circ Res. 1999; 84: 103-112Crossref PubMed Scopus (50) Google Scholar Therefore in the next series of experiments, we assessed the effects of CORM-2 pretreatment on potential modulation of NF-κB-dependent expression of adhesion molecules, E-selectin and ICAM-1, in response to stimulation of HUVECs with the cytokine mixture. As shown in Figure 6, CORM-2 but not its inactive counterpart, iCORM-2, was effective in reducing E-selectin and ICAM-1 expression in TNF-α/INF-γ-stimulated HUVECs, as assessed at the transcription level (reverse transcription-polymerase chain reaction (PCR); Figure 6). The latter changes were accompanied by CORM-2-dependent attenuation of PMN adhesion to TNF-α/INF-γ-stimulated HUVECs (Figure 7).Figure 7Effect of carbon monoxide-releasing molecule (CORM)-2 on neutrophil adhesion in cytokine-stimulated human umbilical vein endothelial cells (HUVECs). HUVECs were grown to confluence in 48-well cell culture plates. They were pretreated with ODQ (10 μmol/l) for 30 min when it applies, then treated with CORM-2 (100 μmol/l) or control (dimethyl sulfoxide (DMSO), inactivated CORM-2) for 1 h. Subsequently, HUVECs were stimulated with cytokines (tumor necrosis factor-α (10 ng/ml) and interferon-γ (10 ng/ml)) for 4 h. Human neutrophils were isolated, labeled with Cr51, and incubated (3 × 106/well) with HUVECs for 1 h. Subsequently, percentage of adherent neutrophils was quantified. Values are mean±s.e.m. n=6 in triplicate. No statistical difference between unstimulated control and other unstimulated groups. *P<0.05 compared with unstimulated control; #P<0.05 compared with cytokine-stimulated control; †P<0.05 compared with their unstimulated counterpart. PMN, polymorphonuclear.View Large Image Figure ViewerDownload (PPT) Although hormonal manipulation of the deceased organ donor has led to increased viable organs during the procurement procedure,38.Novitzky D. Cooper D.K. Rosendale J.D. et al.Hormonal therapy of the brain-dead organ donor: experimental and clinical studies.Transplantation. 2006; 82 (1201): 1396Crossref PubMed Scopus (162) Google Scholar few donor-directed strategies have been used to prevent organ damage. Recently, CO has been shown to have anti-inflammatory effects,7.Nakao A. Choi A.M. Murase N. Protective effect of carbon monoxide in transplantation.J Cell Mol Med. 2006; 10: 650-671Crossref PubMed Scopus (110) Google Scholar and administration of inhaled CO protected rat organs from transplant-related injury.10.Nakao A. Faleo G. Nalesnik M.A. et al.Low dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function.Am J Physiol Renal Physiol. 2009; 207: F19Crossref Scopus (29) Google Scholar, 11.Nakao A. Faleo G. Shimizu H. et al.Ex vivo carbon monoxide prevents cytochrome P450 degradation and ischemia/reperfusion injury of kidney grafts.Kidney Int. 2008; 74: 1009-1016Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 12.Faleo G. Neto J.S. Kohmoto J. et al.Carbon monoxide ameliorates renal cold ischemia-reperfusion injury with an upregulation of vascular endothelial growth factor by activation of hypoxia-inducible factor.Transplantation. 2008; 85: 1833-1840Crossref PubMed Scopus (66) Google Scholar, 13.Martins P.N. Reutzel-Selke A. Jurisch A. et al.Induction of carbon monoxide in donor animals prior to organ procurement reduces graft immunogenicity and inhibits chronic allograft dysfunction.Transplantation. 2006; 82: 938-944Crossref PubMed Scopus (38) Google Scholar, 14.Neto J.S. Nakao A. Kimizuka K. et al.Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide.Am J Physiol Renal Physiol. 2004; 287: F979-F989Crossref PubMed Scopus (180) Google Scholar, 15.Tomiyama K. Ikeda A. Ueki S. et al.Inhibition of Kupffer cell-mediated early proinflammatory response with carbon monoxide in transplant-induced hepatic ischemia/reperfusion injury in rats.Hepatology. 2008; 48: 1608-1620Crossref PubMed Scopus (75) Google Scholar, 16.Kaizu T. Nakao A. Tsung A. et al.Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation.Surgery. 2005; 138: 229-235Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 17.Nakao A. Toyokawa H. Tsung A. et al.Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury.Am J Transplant. 2006; 6: 2243-2255Crossref PubMed Scopus (91) Google Scholar, 18.Nakao A. Kimizuka K. Stolz D.B. et al.Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury.Am J Pathol. 2003; 163: 1587Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 19.Zhou H.C. Ding W.G. Cui X.G. et al.Carbon monoxide inhalation ameliorates conditions of lung grafts from rat brain death donors.Chin Med J (Engl). 2008; 121: 1411-1498PubMed Google Scholar, 20.Kohmoto J. Nakao A. Sugimoto R. et al.Carbon monoxide-saturated preservation solution protects lung grafts from ischemia-reperfusion injury.J Thorac Cardiovasc Surg. 2008; 136: 1067-1075Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 21.Kohmoto J. Nakao A. Stolz D.B. et al.Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway.Am J Transplant. 2007; 7: 2279-2290Crossref PubMed Scopus (97) Google Scholar, 22.Kohmoto J. Nakao A. Kaizu T. et al.Low-dose carbon monoxide inhalation prevents ischemia/reperfusion injury of transplanted rat lung grafts.Surgery. 2006; 140: 179-185Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 23.Nakao A. Toyokawa H. Abe M. et al.Heart allograft protection with low-dose carbon monoxide inhalation: effects on inflammatory mediators and alloreactive T-cell responses.Transplantation. 2006; 81: 220-230Crossref PubMed Scopus (67) Google Scholar Unfortunately, the prospect of using inhaled CO in clinical transplantation is limited due to difficulty in CO storage and delivery in a controlled manner. As well, CO binds to hemoglobin and forms COHb with an affinity 240 times higher than that of oxygen, interfering with oxygen transport and delivery to the organs/tissues with potentially life-threatening consequences.16.Kaizu T. Nakao A. Tsung A. et al.Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation.Surgery. 2005; 138: 229-235Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 24.Nakao A. Kimizuka K. Stolz D.B. et al.Protective effect of carbon monoxide inhalation for cold-preserved small intestinal grafts.Surgery. 2003; 134: 285-292Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Recently, the availability of CORM capable of releasing CO in biological systems in a controlled manner provides the opportunity to investigate CO-mediated biological effects in more detail.39.Motterlini R. Mann B.E. Johnson T.R. et al.Bioactivity and pharmacological actions of carbon monoxide-releasing molecules.Curr Pharm Des. 2003; 9: 2525-2539Crossref PubMed Scopus (230) Google Scholar On a separate note, it is worthwhile to mention that while both routes of CO administration (that is, by inhalation or systemic administration) exhibit anti-inflammatory effects, the use of CO donors in vivo does not result in a dramatic increase in COHb levels, as opposed to inhaled CO.39.Motterlini R. Mann B.E. Johnson T.R. et al.Bioactivity and pharmacological actions of carbon monoxide-releasing molecules.Curr Pharm Des. 2003; 9: 2525-2539Crossref PubMed Scopus (230) Google Scholar, 40.Guo Y. Stein A.B. Wu W.J. et al.Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo.Am J Physiol Heart Circ Physiol. 2004; 286: H1649-H1653Crossref PubMed Scopus (205) Google Scholar, 41.De Backer O. Elinck E. Blanckaert B. et al.Water-soluble CO-releasing molecules reduce the development of postoperative ileus via modulation of MAPK/HO-1 signalling and reduction of oxidative stress.Gut. 2009; 58: 347-356Crossref PubMed Scopus (103) Google Scholar In this regard, it has been recently shown that inhaled CO (20 p.p.m.) increased COHb levels from 1 to 10% in experiments performed on rats,14.Neto J.S. Nakao A. Kimizuka K. et al.Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide.Am J Physiol Renal Physiol. 2004; 287: F979-F989Crossref PubMed Scopus (180) Google Scholar whereas no significant changes in %COHb levels were
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