Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, are chronic, relapsing and remitting inflammatory disorders of the intestinal tract. Because the precise pathogenesis of IBD remains unclear, it is important to investigate the pathogenesis of IBD and to evaluate new anti-inflammatory strategies. Recent accumulating evidence has suggested that carbon monoxide (CO) may act as an endogenous defensive gaseous molecule to reduce inflammation and tissue injury in various organ injury models, including intestinal inflammation. Furthermore, exogenous CO administration at low concentrations is protective against intestinal inflammation. These data suggest that CO may be a novel therapeutic molecule in patients with IBD. In this review, we present what is currently known regarding the therapeutic potential of CO in intestinal inflammation.

1.
Asakura K, Nishiwaki Y, Inoue N, Hibi T, Watanabe M, Takebayashi T: Prevalence of ulcerative colitis and Crohn's disease in Japan. J Gastroenterol 2009;44:659-665.
[PubMed]
2.
Xavier RJ, Podolsky DK: Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007;448:427-434.
[PubMed]
3.
Blonski W, Buchner AM, Lichtenstein GR: Inflammatory bowel disease therapy: current state-of-the-art. Curr Opin Gastroenterol 2011;27:346-357.
[PubMed]
4.
Naito Y, Takagi T, Yoshikawa T: Heme oxygenase-1: a new therapeutic target for inflammatory bowel disease. Aliment Pharmacol Ther 2004;20(suppl 1):177-184.
[PubMed]
5.
Maines MD: The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 1997;37:517-554.
[PubMed]
6.
Morse D, Choi AM: Heme oxygenase-1: from bench to bedside. Am J Respir Crit Care Med 2005;172:660-670.
[PubMed]
7.
Takagi T, Naito Y, Mizushima K, Nukigi Y, Okada H, Suzuki T, Hirata I, Omatsu T, Okayama T, Handa O, Kokura S, Ichikawa H, Yoshikawa T: Increased intestinal expression of heme oxygenase-1 and its localization in patients with ulcerative colitis. J Gastroenterol Hepatol 2008;23(suppl 2):S229-S233.
[PubMed]
8.
Wang WP, Guo X, Koo MW, Wong BC, Lam SK, Ye YN, Cho CH: Protective role of heme oxygenase-1 on trinitrobenzene sulfonic acid-induced colitis in rats. Am J Physiol Gastrointest Liver Physiol 2001;281:G586-G594.
[PubMed]
9.
Harusato A, Naito Y, Takagi T, Uchiyama K, Mizushima K, Hirai Y, Higashimura Y, Katada K, Handa O, Ishikawa T, Yagi N, Kokura S, Ichikawa H, Muto A, Igarashi K, Yoshikawa T: BTB and CNC homolog 1 (bach1) deficiency ameliorates TNBS colitis in mice: role of M2 macrophages and heme oxygenase-1. Inflamm Bowel Dis 2013;19:740-753.
[PubMed]
10.
Higashimura Y, Naito Y, Takagi T, Mizushima K, Hirai Y, Harusato A, Ohnogi H, Yamaji R, Inui H, Nakano Y, Yoshikawa T: Oligosaccharides from agar inhibit murine intestinal inflammation through the induction of heme oxygenase-1 expression. J Gastroenterol 2013;48:897-909.
[PubMed]
11.
Gibbons SJ, Verhulst PJ, Bharucha A, Farrugia G: Review article: carbon monoxide in gastrointestinal physiology and its potential in therapeutics. Aliment Pharmacol Ther 2013;38:689-702.
[PubMed]
12.
Takagi T, Naito Y, Uchiyama K, Yoshikawa T: The role of heme oxygenase and carbon monoxide in inflammatory bowel disease. Redox Rep 2010;15:193-201.
[PubMed]
13.
Piantadosi CA, Sylvia AL, Saltzman HA, Jobsis-Vandervliet FF: Carbon monoxide-cytochrome interactions in the brain of the fluorocarbon-perfused rat. J Appl Physiol 1985;58:665-672.
[PubMed]
14.
Coceani F, Kelsey L, Seidlitz E: Carbon monoxide-induced relaxation of the ductus arteriosus in the lamb: evidence against the prime role of guanylyl cyclase. Br J Pharmacol 1996;118:1689-1696.
[PubMed]
15.
Kajimura M, Fukuda R, Bateman RM, Yamamoto T, Suematsu M: Interactions of multiple gas-transducing systems: hallmarks and uncertainties of CO, NO, and H2S gas biology. Antioxid Redox Signal 2010;13:157-192.
[PubMed]
16.
Dioum EM, Rutter J, Tuckerman JR, Gonzalez G, Gilles-Gonzalez MA, McKnight SL: NPAS2: a gas-responsive transcription factor. Science 2002;298:2385-2387.
[PubMed]
17.
Lee SJ, Ryter SW, Xu JF, Nakahira K, Kim HP, Choi AM, Kim YS: Carbon monoxide activates autophagy via mitochondrial reactive oxygen species formation. Am J Respir Cell Mol Biol 2011;45:867-873.
[PubMed]
18.
Zuckerbraun BS, Chin BY, Bilban M, d'Avila JC, Rao J, Billiar TR, Otterbein LE: Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J 2007;21:1099-1106.
[PubMed]
19.
Nakao A, Faleo G, Shimizu H, Nakahira K, Kohmoto J, Sugimoto R, Choi AM, McCurry KR, Takahashi T, Murase N: Ex vivo carbon monoxide prevents cytochrome p450 degradation and ischemia/reperfusion injury of kidney grafts. Kidney Int 2008;74:1009-1016.
[PubMed]
20.
Ogaki S, Taguchi K, Watanabe H, Ishima Y, Otagiri M, Maruyama T: Carbon monoxide-bound red blood cell resuscitation ameliorates hepatic injury induced by massive hemorrhage and red blood cell resuscitation via hepatic cytochrome p450 protection in hemorrhagic shock rats. J Pharm Sci 2014;103:2199-2206.
[PubMed]
21.
Carvajal JA, Germain AM, Huidobro-Toro JP, Weiner CP: Molecular mechanism of cGMP-mediated smooth muscle relaxation. J Cell Physiol 2000;184:409-420.
[PubMed]
22.
Wang Z, Yue P, Lin DH, Wang WH: Carbon monoxide stimulates Ca2+-dependent big-conductance K channels in the cortical collecting duct. Am J Physiol Renal Physiol 2013;304:F543-F552.
[PubMed]
23.
Liu H, Mount DB, Nasjletti A, Wang W: Carbon monoxide stimulates the apical 70-pS K+ channel of the rat thick ascending limb. J Clin Invest 1999;103:963-970.
[PubMed]
24.
Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, Choi AM, Soares MP: Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med 2000;192:1015-1026.
[PubMed]
25.
Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, Soares MP: Heme oxygenase-1-derived carbon monoxide requires the activation of transcription factor NF-κβ to protect endothelial cells from tumor necrosis factor-α-mediated apoptosis. J Biol Chem 2002;277:17950-17961.
[PubMed]
26.
Zhang X, Shan P, Otterbein LE, Alam J, Flavell RA, Davis RJ, Choi AM, Lee PJ: Carbon monoxide inhibition of apoptosis during ischemia-reperfusion lung injury is dependent on the p38 mitogen-activated protein kinase pathway and involves caspase 3. J Biol Chem 2003;278:1248-1258.
[PubMed]
27.
Queiroga CS, Almeida AS, Alves PM, Brenner C, Vieira HL: Carbon monoxide prevents hepatic mitochondrial membrane permeabilization. BMC Cell Biol 2011;12:10.
[PubMed]
28.
Queiroga CS, Almeida AS, Martel C, Brenner C, Alves PM, Vieira HL: Glutathionylation of adenine nucleotide translocase induced by carbon monoxide prevents mitochondrial membrane permeabilization and apoptosis. J Biol Chem 2010;285:17077-17088.
[PubMed]
29.
Chung SW, Liu X, Macias AA, Baron RM, Perrella MA: Heme oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice. J Clin Invest 2008;118:239-247.
[PubMed]
30.
Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM: Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 2000;6:422-428.
[PubMed]
31.
Sarady JK, Otterbein SL, Liu F, Otterbein LE, Choi AM: Carbon monoxide modulates endotoxin-induced production of granulocyte macrophage colony-stimulating factor in macrophages. Am J Respir Cell Mol Biol 2002;27:739-745.
[PubMed]
32.
Reed JA, Whitsett JA: Granulocyte-macrophage colony-stimulating factor and pulmonary surfactant homeostasis. Proc Assoc Am Physicians 1998;110:321-332.
[PubMed]
33.
Parkes GC, Whelan K, Lindsay JO: Smoking in inflammatory bowel disease: impact on disease course and insights into the aetiology of its effect. J Crohns Colitis 2014;8:717-725.
[PubMed]
34.
Lunney PC, Leong RW: Review article: ulcerative colitis, smoking and nicotine therapy. Aliment Pharmacol Ther 2012;36:997-1008.
[PubMed]
35.
Otterbein LE, Mantell LL, Choi AM: Carbon monoxide provides protection against hyperoxic lung injury. Am J Physiol 1999;276:L688-L694.
[PubMed]
36.
Kaizu T, Nakao A, Tsung A, Toyokawa H, Sahai R, Geller DA, Murase N: Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation. Surgery 2005;138:229-235.
[PubMed]
37.
Nakao A, Toyokawa H, Abe M, Kiyomoto T, Nakahira K, Choi AM, Nalesnik MA, Thomson AW, Murase N: Heart allograft protection with low-dose carbon monoxide inhalation: effects on inflammatory mediators and alloreactive T-cell responses. Transplantation 2006;81:220-230.
[PubMed]
38.
Takagi T, Naito Y, Inoue M, Akagiri S, Mizushima K, Handa O, Kokura S, Ichikawa H, Yoshikawa T: Inhalation of carbon monoxide ameliorates collagen-induced arthritis in mice and regulates the articular expression of IL-1β and MCP-1. Inflammation 2009;32:83-88.
[PubMed]
39.
Hegazi RA, Rao KN, Mayle A, Sepulveda AR, Otterbein LE, Plevy SE: Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1-dependent pathway. J Exp Med 2005;202:1703-1713.
[PubMed]
40.
Sheikh SZ, Hegazi RA, Kobayashi T, Onyiah JC, Russo SM, Matsuoka K, Sepulveda AR, Li F, Otterbein LE, Plevy SE: An anti-inflammatory role for carbon monoxide and heme oxygenase-1 in chronic Th2-mediated murine colitis. J Immunol 2011;186:5506-5513.
[PubMed]
41.
Takagi T, Naito Y, Mizushima K, Akagiri S, Suzuki T, Hirata I, Omatsu T, Handa O, Kokura S, Ichikawa H, Yoshikawa T: Inhalation of carbon monoxide ameliorates TNBS-induced colitis in mice through the inhibition of TNF-α expression. Dig Dis Sci 2010;55:2797-2804.
[PubMed]
42.
Zuckerbraun BS, Otterbein LE, Boyle P, Jaffe R, Upperman J, Zamora R, Ford HR: Carbon monoxide protects against the development of experimental necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2005;289:G607-G613.
[PubMed]
43.
Motterlini R, Clark JE, Foresti R, Sarathchandra P, Mann BE, Green CJ: Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities. Circ Res 2002;90:E17-E24.
[PubMed]
44.
Katada K, Bihari A, Mizuguchi S, Yoshida N, Yoshikawa T, Fraser DD, Potter RF, Cepinskas G: Carbon monoxide liberated from co-releasing molecule (CORM-2) attenuates ischemia/reperfusion (I/R)-induced inflammation in the small intestine. Inflammation 2010;33:92-100.
[PubMed]
45.
Fukuda W, Takagi T, Katada K, Mizushima K, Okayama T, Yoshida N, Kamada K, Uchiyama K, Ishikawa T, Handa O, Konishi H, Yagi N, Ichikawa H, Yoshikawa T, Cepinskas G, Naito Y, Itoh Y: Anti-inflammatory effects of carbon monoxide-releasing molecule on trinitrobenzene sulfonic acid-induced colitis in mice. Dig Dis Sci 2014;59:1142-1151.
[PubMed]
46.
Takagi T, Naito Y, Uchiyama K, Suzuki T, Hirata I, Mizushima K, Tsuboi H, Hayashi N, Handa O, Ishikawa T, Yagi N, Kokura S, Ichikawa H, Yoshikawa T: Carbon monoxide liberated from carbon monoxide-releasing molecule exerts an anti-inflammatory effect on dextran sulfate sodium-induced colitis in mice. Dig Dis Sci 2011;56:1663-1671.
[PubMed]
47.
Joe Y, Uddin MJ, Zheng M, Kim HJ, Chen Y, Yoon NA, Cho GJ, Park JW, Chung HT: Tristetraprolin mediates anti-inflammatory effect of carbon monoxide against DSS-induced colitis. PLoS One 2014;9:e88776.
[PubMed]
48.
Uddin MJ, Jeong SO, Zheng M, Chen Y, Cho GJ, Chung HT, Joe Y: Carbon monoxide attenuates dextran sulfate sodium-induced colitis via inhibition of GSK-3β signaling. Oxid Med Cell Longev 2013;2013:210563.
[PubMed]
49.
Onyiah JC, Sheikh SZ, Maharshak N, Steinbach EC, Russo SM, Kobayashi T, Mackey LC, Hansen JJ, Moeser AJ, Rawls JF, Borst LB, Otterbein LE, Plevy SE: Carbon monoxide and heme oxygenase-1 prevent intestinal inflammation in mice by promoting bacterial clearance. Gastroenterology 2013;144:789-798.
[PubMed]
50.
Uchiyama K, Naito Y, Takagi T, Mizushima K, Hayashi N, Harusato A, Hirata I, Omatsu T, Handa O, Ishikawa T, Yagi N, Kokura S, Yoshikawa T: Carbon monoxide enhance colonic epithelial restitution via FGF15 derived from colonic myofibroblasts. Biochem Biophys Res Commun 2010;391:1122-1126.
[PubMed]
51.
Takagi T, Naito Y, Uchiyama K, Okuda T, Suzuki T, Tsuboi H, Mizushima K, Handa O, Yagi N, Ichikawa H, Yoshikawa T: Colonic insufflation with carbon monoxide gas inhibits the development of intestinal inflammation in rats. Med Gas Res 2012;2:23.
[PubMed]
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