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doi:10.1111/jgh.12742
O R I G I N A L A RT I C L E
Therapeutic roles of carbon monoxide in intestinal ischemia-reperfusion injury Kazuhiro Katada, Tomohisa Takagi, Kazuhiko Uchiyama and Yuji Naito Molecular Gastroenterology and Hepatology, Graduate School of Medial Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Key words carbon monoxide, cytoprotection, heme oxygenase, ischemia-reperfusion injury, oxidative stress. Correspondence Kazuhiro Katada, Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan. Email:
[email protected] Conflicts of interest No potential conflict of interest has been declared by the authors.
Abstract Intestinal ischemia-reperfusion (I-R) injury is a complex, multifactorial, pathophysiological process with high morbidity and mortality, leading to serious difficulty in treatment. The mechanisms involved in the pathogenesis of intestinal I-R injury have been examined in detail and various therapeutic approaches for intestinal I-R injury have been developed; however, existing circumstances have not yet led to a dramatic change of treatment. Carbon monoxide (CO), one of the by-products of heme degradation by heme oxygenase (HO), is considered as a candidate for treatment of intestinal I-R injury and indeed HO-1-derived endogenous CO and exogenous CO play a pivotal role in protecting the gastrointestinal tract from intestinal I-R injury. Interestingly, anti-inflammatory effects of CO have been elucidated sufficiently in various cell types including endothelial cells, circulating leukocytes, macrophages, lymphocytes, epithelial cells, fibroblast, organ-specific cells, and immune-presenting cells. In this review, we herein focus on the therapeutic roles of CO in intestinal I-R injury and the cell-specific anti-inflammatory effects of CO, clearly demonstrating future therapeutic strategies of CO for treating intestine I-R injury.
Introduction Intestinal ischemia-reperfusion (I-R) injury, a life-threatening abdominal emergency, occurs in a variety of clinical settings, including mesenteric artery occlusion, mesenteric venous thrombosis, major cardiovascular surgery, trauma, shock, and small intestinal transplantation, and has high morbidity and mortality.1,2 The mechanisms involved in the pathogenesis of intestinal I-R injury have been particularly investigated. Various cytoprotective mediators including nitric oxide (NO), prostaglandins, glycine, arginine, hydrogen sulfide, and heat shock proteins (HSPs) have been investigated as a therapeutic target for intestinal I-R injury. However, existing circumstances have not yet led to a dramatic change of treatment. Carbon monoxide (CO) is traditionally best known as an odorless and toxic gas; however, it is recently accepted to have a beneficial effect in various inflammation models. CO is one of the three by-products of heme degradation by inducible heme oxygenase (HO-1) (Fig. 1) and constitutive heme oxygenase-2 and -3 (HO-2 and HO-3), the other two being Fe2+ and biliverdin.3,4 CO has recently been accepted as a cytoprotective molecule in various disease models. HO-1-derived endogenous CO and exogenous CO have antiapoptotic effects in both animal and cell culture models.5 CO also exhibits anti-inflammatory effects in both types of models, not only inhibiting the production of pro-inflammatory cytokines6 but also increasing the production of anti-inflammatory 46
cytokines.7 These anti-inflammatory effects of CO are demonstrated via modulation of nuclear factor kappa B (NF-κB),8 p38 mitogen-activated protein kinase (MAPK),9 mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2,10 and the toll-like receptor (TLR)11 signaling pathways. Interestingly enough, CO is closely interacted with other cytoprotective mediators such as NO, prostaglandin, and HSPs. CO is known to function in the similar way of NO, since both CO and NO are capable of activating the same intracellular target, soluble guanylyl cyclase (sGC). It is surprising to note that some effects of CO are independent of sGC. CO is also shown to downmodurate NO synthesis12 or mediate prostaglandin E2.13 Given the interaction between CO and HSPs, it has been shown that CO ameliorated I-R injury with increased HSP70 expression14 and HSP70 also mediated the cytoprotective effects of CO.15 Originally, CO inhalation was a straightforward delivery method of CO, showing anti-inflammatory effects in various models.9–11,16–18 However, CO inhalation also induces elevation of the carboxyhemoglobin (COHb) concentration, which is generally harmful to cells and animals. Therefore, different types of CO delivery systems are urgently required, including CO-releasing molecule (CORM) and CO-bubbling (containing) solution. Unfortunately, CORM and CO-bubbling solution cannot resolve all issues regarding safe and effective CO delivery systems at this moment. Recently, new types of CORM (containing Mn or PhotoCORMs) are starting to emerge for research.19,20 Ongoing
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Therapeutic roles of carbon monoxide
HSF1 NF-κB AP-1 Nrf2 Bach1 Heme
Heme oxygenase-1 CO
Biliverdin
Fe
Bilirubin
Biliverdin reductase Figure 1 Heme oxygenase/carbon monoxide (CO) system. AP-1, activator protein-1; Bach1, BTB and CNC homolog 1; HSF-1, heat shock factor-1; NF-κB, nuclear factor kappa B; Nrf2, NF-E2-related factor 2.
and future research of CORM should be expected to resolve these issues for a clinical application. Interestingly, the anti-inflammatory effects of CO have been investigated in various cell types, including endothelial cells (ECs), circulating leukocytes, macrophages, lymphocytes, epithelial cells, fibroblast, organ-specific cells, and immune-presenting cells. These participating cells are intimately related to each other in the mechanisms. In this review, we herein focus on the therapeutic roles of CO in intestinal I-R injury and the cell-specific anti-inflammatory effects of CO, especially in ECs, macrophages, lymphocytes, polymorphonuclear leukocytes (PMN), and epithelial cells.
CO delivery systems As mentioned, CO can be delivered by inhalation, CORM, and CO-bubbling solution. Initially, exogenous administration of CO via inhalation showed important cytoprotective function and suppressed the inflammatory response associated with various disease states and conditions such as I-R injury,9,16 hyperoxia,17 organ transplantation,18 experimental colitis,21 and postoperative ileus.22 In intestinal inflammation, exogenous CO also reduces the severity of disease activity.17,23 However, such method of CO administration is associated with increased formation of COHb, both in rodents10 and humans,24 thus presenting a potential drawback in the use of gaseous CO for therapeutic purposes. Transitional metal carbonyls (i.e. CORMs) have been recently used to deliver CO in a controlled manner without altering COHb levels.25 As a consequence, these molecules have received increasing attention for their potential pharmaceutical application.26 In regard to the latter, CORMs have been shown to act pharmacologically in rat aortic and cardiac tissue where CORM-liberated CO induced vasorelaxant effects25 and decreased myocardial I-R damage.27 Moreover, CORM-liberated CO interferes with PMN recruitment to the liver and small intestine during systemic inflam-
mation in mice inflicted by polymicrobial sepsis or thermal (burn) injury.28 It appears that at the cellular level the anti-inflammatory effects of CORM-derived CO are associated with prevention of cell activation with respect to reduced production of reactive oxygen species (ROS) by vascular ECs,28 lipopolysaccharide (LPS)-stimulated macrophages29 and PMN,30 and suppression of the pro-adhesive phenotype in LPS-stimulated ECs28 and plateletactivating factor-activated PMN.30 CO-bubbling solutions have also been developed for CO delivery. Nakao et al. demonstrated that ex vivo CO delivery into University of Wisconsin solution was a simple and innovative therapeutic strategy to prevent transplant-induced I-R injury through activation of sGC.31 This application of ex vivo CO delivery has been further extended to other disease models such as renal I-R injury and vein graft through activation of the hypoxiainducible factor-1 α/vascular endothelial growth factor pathway.32 Moreover, CO-bubbling solutions are considered as the oral or anal administrations of CO, providing new insight into the application of CO in gastrointestinal tract. HO is the rate-limiting enzyme in heme catabolism and leads to the generation of CO as well as biliverdin and free iron. Therefore, HO inducers are considered as a candidate for a CO delivery system, including hemin, cobalt protoporphyrin (CoPP), and other reagents such as glutamine, octreotide, and lansoprazole.33,34 These reagents are known to upregulate the expression of HO-1, exhibiting cytoprotective and anti-inflammatory effects. It is interesting to note that the transcriptional factors of HO-1 have attracted interest as another type of CO delivery system. As is well known, HO-1 is upregulated by various transcription factors including heat shock factor-1, NF-κB, activator protein-1, and NF-E2-related factor 2 (Nrf2)35 (Fig. 1). On the contrary, BTB and CNC homolog 1 (Bach1) has been shown to be a transcriptional repressor of HO-1.36 In normal condition, Bach1 combines to small Maf protein in the nucleus, repressing HO-1 transcription. When oxidative stress occurs, Bach1 is exported from the nucleus and Nrf2 is imported into the nucleus and combines to small Maf protein, inducing HO-1 transcription. The mechanism suggests that Nrf2 and Bach1 closely regulate each other to regulate HO-1 expression.36 Moreover, Nrf2 is upregulated by various foods including sulforaphane contained in broccoli.37 Employing Bach1deficient mice, Bach1 deficiency also augments the expression of HO-1 and exhibits anti-inflammatory effects in pressure overload model38 and indomethacin-induced intestinal injury.39 Of the transcriptional factors for HO-1, the activator of Nrf2 or inhibitor of Bach1 should be notably developed as a new HO-1 inducer.
Intestinal I-R injury Intestinal ischemia, including acute mesenteric ischemia, chronic mesenteric ischemia, and ischemic colitis, is a life-threatening abdominal emergency and remains a diagnostic challenge.1,2 Rapid diagnosis and treatment to prevent substantial bowel infarction are generally required. In-hospital mortality rates have remained high over the past few decades. I-R injury occurs in a variety of clinical settings mentioned above. Moreover, patients who have a history of congestive heart disease, cardiac arrhythmia, atherosclerosis, diabetes, hyperlipidemia, hypovolemia, hypotension, recent surgery, deep venous thromboses, arterial embolism, or collagen disease show a high risk of intestinal ischemia.1,2 The common
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clinical features of these diseases are caused by impaired blood perfusion of the intestine, the hypoxia-associated subsequent complications, and local/systemic inflammation.40 Intestinal ischemia rapidly progresses to tissue necrosis followed by barrier dysfunction and bacterial translocation, and subsequently leads to a series of events that result in systemic responses, including systemic inflammatory response syndrome and multiple organ failure.41 Regarding the mechanism of intestinal I-R, it is characterized by two different stages: ischemia and then reperfusion of the ischemic intestine (Fig. 2). The ischemic stage induces lack of oxygen, resulting in decreased production of ATP, which in turn leads to alterations in intracellular calcium concentrations and activation of cytotoxic enzymes, resulting in cell damage. On the other hand, reperfusion of ischemic tissue causes increased production of oxygen radicals as oxygen reacts with hypoxanthine and xanthine oxidase to generate superoxide anion and hydrogen peroxide. Oxygen radicals consequently induce epithelial barrier dysfunction and tissue injury.42,43 Intestinal I-R injury elicits a molecular and cellular inflammatory response within the intestine, including activation of inflammation-relevant transcription factor, NF-κB, and recruitment of PMN.43,44 NF-κB is a ubiquitous, rapidly acting transcription factor involved in immune and inflammatory reactions. It has been implicated in the regulation of a number of gene products that contribute to further amplification of inflammation, including induction of EC adhesion molecules and pro-inflammatory cytokine expressions.45 Moreover, high mobility group box 1 (HMGB1), recently known as an important late mediator of endotoxic shock, sepsis, or other diseases, is also significantly elevated following intestinal I-R injury.46 The activation and recruitment of PMN is a rate-limiting event in the pathogenesis of I-R injury. Increased accumulation of PMN
NF-κB
in the I-R-challenged intestine further contributes to intestinal tissue damage, leading to bacterial translocation and subsequent systemic complications.47 However; anti-PMN antiserum treatment offers only limited protection, which indicates that other inflammatory cells may be involved. It has recently been shown that resident macrophages play an important role in early mucosal damage in intestinal I-R injury.48 Furthermore, ECs are known to be sensitive to hypoxia. Macrophage and ECs are therefore involved in the pathophysiology of intestinal I-R injury. Taken together, the acute phase of intestinal I-R injury is clearly characterized by oxidative stress-related inflammation and leukocyte involvements. The consideration of therapeutic targets should be based on the pathophysiology of intestinal I-R injury. To attenuate oxidative stress and leukocyte involvement is most important in the protection from intestinal I-R injury.
Cell-type-specific anti-inflammatory effects of CO HO-1 is expressed in all cells and tissues; however, its pivotal anti-inflammatory effects and catalytic by-product, CO, appear to be dependent on cell-type-specific functions in myeloid cells, ECs, and epithelial cells (Fig. 3). Myeloid cells are composed of monocytes, macrophages, lymphocytes, and dendritic cells and play crucial regulatory roles in the innate and adaptive immune systems. Macrophages function as a first line of defense against invading microorganisms and are activated by various immunological stimuli such as microbial products and various cytokines.49 In rodent macrophages, HO-1 has been shown to be upregulated by LPS.50 Expression of monocyte chemoattractant protein-1, by which monocyte activation/ migration is mediated as one of the earliest and important events in the pathogenesis of atherosclerosis, is inhibited by induction of HO-1 in cultured macrophages.51 Some evidence has indicated that CO inhalation mediates cellular cytoprotection via its antiinflammatory properties in LPS-induced macrophages,8 and that
NF-κB Antiapoptotic
Figure 2 Mechanisms of intestinal ischemia-reperfusion injury. (↑) increased; (↓) decreased. ATP, adenosine triphosphate; Ca, calcium; HMGB1, high mobility group box 1; NF-κB, nuclear factor kappa B.
48
Figure 3 Multiple effects of carbon monoxide (CO) for therapeutic potential in intestinal inflammation. (↑) increased; (↓) decreased. eNOS, endothelial nitric oxide synthase; FGF, fibroblast growth factor; KC, keratinocyte chemoattractant; NF-κB, nuclear factor kappa B; ROS, reactive oxygen species; Th-2, T helper cells-2; TNF, tumor necrosis factor.
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CORM-derived CO can inhibit the expression of inflammatory cytokines and increase the expression of anti-inflammatory cytokines in both LPS-stimulated7 and cultured macrophages.29 Recently, CO liberated from CORM has been shown to significantly suppress the release of HMGB1 in TLR-activated macrophages through interferon β/Janus kinase 2/signal transducer and activator of transcription 1 signaling pathway.52 HMGB1 is originally known as a nonhistone DNA binding chromosomal protein; however, it is recently considered as a cytokine mediator of inflammation. Recent studies clearly suggest that CO can neutralize HMGB1 to confer protection against damage and tissue injury during various diseases. Moreover, some study has demonstrated attenuating effects of CO with respect to ROS production in stimulated macrophages.53 Effects of CO on ROS production should be further investigated. Interestingly, HO-1-derived CO has been shown to enhance the host defense response to microbial sepsis in mice through increased rate of phagocytosis by macrophages.54 More recently, it has been reported that CO confers protection in sepsis by enhancing autophagy and phagocytosis.55 CO-mediated effects on phagocytosis and autophagy are quite new and hot topic. Ongoing and future investigations could be expected to elucidate these mechanisms. One of the hallmarks of inflammation as a consequence of mechanical trauma, transplantation, I-R, or bacterial infection is an increase in PMN accumulation in the affected organs. PMN recruitment to the affected organs is a complex multistep process and involves the activation of both vascular endothelium and leukocytes, with subsequent upregulation of the pro-adhesive phenotype, which, in turn, results in the initiation of adhesive interactions (rolling, firm adhesion, and migration) between PMNs and vascular ECs.56 Originally, the induction of HO-1 was shown to suppress both venular leukocyte adhesion elicited by oxidative stress57 and leukocyte accumulation in liver.58 Since then, CO inhalation has been shown to attenuate inflammatory responses via the inhibition of PMN accumulation.10 CORM-released CO also ameliorates PMN transendothelial migration.28 Although some studies have demonstrated attenuating effects of CO with respect to ROS production in stimulated PMNs,59 others have confirmed increased ROS production in PMNs in the presence of CORMreleased CO.60 More recently, CORM-released CO, although further amplifying ROS production and degranulation of PMNs in sepsis, concurrently reduced the levels of cell surface-bound elastase, which contributes to suppression of PMN transendothelial migration.61 Further investigations in this field should be expected. Lymphocytes are also intimately involved in the pathogenesis of intestinal inflammation, including I-R injury and experimental colitis. It has been reported that the production of tumor necrosis factor alpha (TNF-α) was significantly inhibited in CD4+ T cells isolated from mice treated with CO inhalation,21 and that CO suppressed chronic Th2-mediated murine colitis via induction of interleukin (IL)-10.23,62 Furthermore, recent study indicates that HO-1, CO, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells (Tregs).63 These studies clearly demonstrate that HO-1 and CO can modulate lymphocytes including Th1, Th2, or Tregs to have therapeutic effects in a variety of disorders involving inflammation and immune responses. ECs closely interact with PMN during inflammation-mediated PMN transmigration, whereby the expressions of adhesion molecules are upregulated. CO as well as HO-1 can reduce the expres-
Therapeutic roles of carbon monoxide
sion of adhesion molecules via downregulation of NF-κB.28,64 CORM-3-derived CO can control PMN migration directly by modulating both the activity of intracellular superoxide dismutase (SOD) and the binding of extracellular SOD to the cell surface.65 CO also has an antiapoptotic effect in ECs via activation of the p38 MAPK signaling5 and phosphatidylinositol 3-kinase/Akt signaling pathways.66 More recently, it has been shown that CORM-3derived CO independently downregulates vascular cell adhesion molecule-1 and E-selectin expression by inhibiting sustained NF-κB activation67 and effectively blocking IL-18 signaling and reducing IL-18-dependent vascular injury and inflammation.68 These studies strongly support that CO plays a pivotal role in the modulation of pro-adhesive phenotype. As mentioned above, CO has been shown to play an important role in macrophages, PMNs, lymphocytes, and ECs, reducing intestinal/other inflammation. Wound healing following inflammation has been reported to be an important factor for the treatment of intestinal inflammation. The effects of CO on colonic epithelial cell restitution have been reported.69 Submucosal myofibroblasts have been suggested to play a very important role in epithelial cell restitution via transforming growth factor-β secretion. In that study, CO increased colonic epithelial cell restitution via the induction of fibroblast growth factor 15 expressions in colonic myofibroblasts. There is another report on CO and wound healing in which an open excision-type wound model was used70; it was found that CORM2-treated wounds contracted significantly faster than inactiveCORM-2-treated wounds. These results indicate that CO may contribute to colonic epithelial restitution under inflammatory conditions. Furthermore, it has been reported that CORM-2 treatment significantly reduced dextran sulfate sodium-induced colitis via the downregulation of cytokines such as keratinocyte chemoattractant (KC), a functional homolog of IL-8, and TNF-α.71 In that study, TNF-α-induced KC production in colonic epithelial cells was inhibited by CORM-2 treatment, indicating that CO liberated from CORM-2 attenuates colonic inflammation via the decreased chemokine production from the epithelial cells. To put them all together, it is well accepted that CO derived from endogenous HO-1, exogenous CO, or CORMs can elicit significant anti-inflammatory effects in specific cells including macrophages, PMNs, lymphocytes, ECs, and epithelial cells.
Therapeutic roles of CO in intestinal I-R injury Many reports have confirmed the antioxidant, anti-inflammatory, and cytoprotective effects of HO-1 inducers, which subsequently produce CO, and CO inducers on small intestinal injuries induced by I-R (Table 1). In those studies, HO-1 is upregulated by various treatments including hypothermia, hypertonic saline, hyperthermia, CoPP, ischemic preconditioning, octreotide, hydrogen sulfide, hydrogen, sulforaphane, hemin, bilirubin, and glutamine, with all protecting against intestinal I-R injury, through a variety of mechanisms including cytoprotection, antiapoptotic, antioxidant, and anti-inflammatory effects as well as decreased leukocyte infiltration/leukocyte-endothelial interaction, Nrf2 upregulation, and NF-κB downregulation.37,72,73 These reports clearly suggest that HO-induced endogenous CO can attenuate intestinal I-R injury. CO itself functions as a signaling molecule that exerts significant cytoprotection because of its anti-inflammatory, vasodilating,
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Table 1
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Effects of heme oxygenase (HO)/carbon monoxide (CO) inducers in intestinal ischemia-reperfusion injury
HO/CO inducer HO inducer PEP-1-HO-1 fusion protein Hydrogen sulfide donor Octreotide Hydrogen bubbled preservation Sulforaphane Ischemic preconditioning Hydrogen sulfide Peroxynitrite decomposition catalyst CoPP Pyrrolidine dithiocarbamate Ischemic preconditioning Hyperthermia Hypertonic saline Hemin Hypothermia Hypothermia Preconditioning Bilirubin Bilirubin Glutamine CO inducer CORM-2 CO in University of Wisconsin solution CO inhalation CO inhalation CO inhalation
Mechanisms
Study
Antioxidant, antiapoptotic Anti-inflammatory Cytoprotection Antioxidant Nrf2↑ Leukocyte-endothelial interactions↓ eNOS↑ Neutrophil infiltration↓ Cytoprotection Leukocyte-endothelial interactions↓ Microcirculation↑ Cytoprotection Cytoprotection MPO↓ Cytoprotection NF-κB↓ Cytoprotection Antioxidant Antioxidant Cytoprotection
Xiang-Hu et al. 2013 Zuidema et al. 2012 Takano et al. 2012 Buchholz et al. 2011 Zhao et al. 2010 Mallick et al. 2010 Yusof et al. 2009 Stefanutti et al. 2007 Wasserberg et al. 2007 Mallick et al. 2006 Mallick et al. 2005 Sakamoto et al. 2005 Attuwaybi et al. 2004 Attuwaybi et al. 2004 Attuwaybi et al. 2003 Hassoun et al. 2002 Tamion et al. 2002 Hammerman et al. 2002 Ceran et al. 2001 Tamaki et al. 1999
NFκB↓, leukocyte-endothelial interactions↓ Soluble guanylyl cyclase (sGC)↑ Soluble guanylyl cyclase (sGC)↑ IL-6↓, iNOS↓ Blood flow↑
Katada et al. 2010 Nakao et al. 2005 Nakao et al. 2003 Nakao et al. 2003 Nakao et al. 2003
(↑) increased; (↓) decreased. CO, carbon monoxide; CoPP, cobalt protoporphyrin; CORM, CO-releasing molecule; eNOS, endothelial nitric oxide synthase; HO, heme oxygenase; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; MPO, myeloperoxidase; NF-κB, nuclear factor kappa B; Nrf2, NF-E2-related factor 2; Pep-1, penetrating peptide; sGC, soluble guanylyl cyclase.
and antiapoptotic properties.7 Exogenous administration of CO via inhalation (250 ppm) was originally thought to be beneficial against I-R-induced intestinal injury through activation of sGC.16,18 Other reports also indicate that CO protects I-R-induced intestinal injury via reducing IL-6 and inducible nitric oxide synthase or increasing blood flow (Table 1). CO inhalation is a straightforward delivery method for utilization of the HO systems; however, excessive CO is toxic and has the important problem of increasing the COHb levels. Therefore, alternative ways of delivering CO need to be developed, one being ex vivo application of CO gas. Cold storage in a preservation solution that is bubbled with 5% CO has been shown to prevent transplant-induced I-R injury,31 clearly suggesting a clinical application of CO for intestinal transplantation. Another way of delivering CO is CORM, which does not elevate COHb levels. Our recent study indicates that CORM-2-released CO confers anti-inflammatory effects on the I-R-challenged intestinal injury in mice by interfering with NF-κB activation and subsequent upregulation of vascular pro-adhesive phenotype.74 Our preliminary study also indicated that a water-soluble CORM-3 exerts anti-inflammatory effects on I-R-challenged intestinal injury in mice. Both types of CORMs clearly indicate protective effects of CO on I-R-induced intestinal injury. However, both CORMs contain a heavy metal in the central part of the 50
compound, anticipating a new type of CORM with no heavy metal. A new type of CORM will lay a path to a new age in the field of CO research. Taken together, it is fundamentally clear that HO-1-derived endogenous CO and exogenous CO can confer anti-inflammatory and cytoprotective effects in I-R-challenged intestinal injury; however, current CO delivery systems are not sufficient for delivering CO more safely and efficiently. Further studies are required for its clinical application.
Conclusion Intestinal I-R injury is a complex, multifactorial, pathophysiological process leading to serious difficulty in treatment. Therapeutic approaches for intestinal I-R injury have been developed; however, these are not appropriate for treating patients with intestinal I-R injury. CO, an important physiological regulator of gastrointestinal function, is a candidate for treatment of intestinal I-R injury and indeed plays a pivotal role in protecting the gastrointestinal tract from intestinal I-R injury as we have described. The mechanisms by which CO works are not fully investigated and understanding these pathways better is necessary to further refine the therapeutic approach. Though we have to overcome several obstacles such as
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the safety of handling CO and high efficacy in future clinical trials with CO, this review clearly demonstrates future therapeutic strategies of CO for treating intestine I-R injury.
References 1 Acosta S. Epidemiology of mesenteric vascular disease: clinical implications. Semin. Vasc. Surg. 2010; 23: 4–8. 2 Yasuhara H. Acute mesenteric ischemia: the challenge of gastroenterology. Surg. Today 2005; 35: 185–95. 3 Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu. Rev. Pharmacol. Toxicol. 1997; 37: 517–54. 4 McCoubrey WK Jr, Huang TJ, Maines MD. Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur. J. Biochem. 1997; 247: 725–32. 5 Brouard S, Otterbein LE, Anrather J et al. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J. Exp. Med. 2000; 192: 1015–26. 6 Morse D, Sethi J. Carbon monoxide and human disease. Antioxid. Redox Signal. 2002; 4: 331–8. 7 Otterbein LE, Bach FH, Alam J et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat. Med. 2000; 6: 422–8. 8 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: 739–45. 9 Amersi F, Shen XD, Anselmo D et al. Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. Hepatology 2002; 35: 815–23. 10 Kaizu T, Ikeda A, Nakao A et al. Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation. Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 294: G236–44. 11 Nakahira K, Kim HP, Geng XH et al. Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts. J. Exp. Med. 2006; 203: 2377–89. 12 Hervera A, Leánez S, Negrete R, Motterlini R, Pol O. Carbon monoxide reduces neuropathic pain and spinal microglial activation by inhibiting nitric oxide synthesis in mice. PLoS ONE 2012; 7: e43693. 13 Horváth B, Hortobágyi L, Lenzsér G et al. Carbon monoxide-prostaglandin E2 interaction in the hypothalamic circulation. Neuroreport 2008; 19: 1601–4. 14 Lee LY, Kaizu T, Toyokawa H et al. Carbon monoxide induces hypothermia tolerance in Kupffer cells and attenuates liver ischemia/reperfusion injury in rats. Liver Transpl. 2011; 17: 1457–66. 15 Kim HP, Wang X, Zhang J et al. Heat shock protein-70 mediates the cytoprotective effect of carbon monoxide: involvement of p38 beta MAPK and heat shock factor-1. J. Immunol. 2005; 175: 2622–9. 16 Nakao A, Kimizuka K, Stolz DB et al. Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury. Am. J. Pathol. 2003; 163: 1587–98. 17 Otterbein LE, Mantell LL, Choi AM. Carbon monoxide provides protection against hyperoxic lung injury. Am. J. Physiol. 1999; 276: L688–94. 18 Nakao A, Moore BA, Murase N et al. Immunomodulatory effects of inhaled carbon monoxide on rat syngeneic small bowel graft motility. Gut 2003; 52: 1278–85. 19 Pfeiffer H, Rojas A, Niesel J, Schatzschneider U. Sonogashira and “click” reactions for the N-terminal and side-chain functionalization
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20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
of peptides with (Mn[CO]3[tpm])+-based CO releasing molecules (tpm = tris(pyrazolyl)methane). Dalton Trans. 2009; 14: 4292–8. Govender P, Pai S, Schatzschneider U, Smith GS. Next generation PhotoCORMs: polynuclear tricarbonylmanganese(I)-functionalized polypyridyl metallodendrimers. Inorg. Chem. 2013; 52: 5470–8. Takagi T, Naito Y, Mizushima K et al. Inhalation of carbon monoxide ameliorates TNBS-induced colitis in mice through the inhibition of TNF-alpha expression. Dig. Dis. Sci. 2010; 55: 2797–804. Moore BA, Overhaus M, Whitcomb J et al. Brief inhalation of low-dose carbon monoxide protects rodents and swine from postoperative ileus. Crit. Care Med. 2005; 33: 1317–26. 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: 1703–13. Mayr FB, Spiel A, Leitner J et al. Effects of carbon monoxide inhalation during experimental endotoxemia in humans. Am. J. Respir. Crit. Care Med. 2005; 171: 354–60. 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: E17–24. Motterlini R, Mann BE, Johnson TR, Clark JE, Foresti R, Green CJ. Bioactivity and pharmacological actions of carbon monoxide-releasing molecules. Curr. Pharm. Des. 2003; 9: 2525–39. Clark JE, Naughton P, Shurey S et al. Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ. Res. 2003; 93: e2–8. Cepinskas G, Katada K, Bihari A, Potter RF. 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: G184–91. Sawle P, Foresti R, Mann BE, Johnson TR, Green CJ, Motterlini R. Carbon monoxide-releasing molecules (CO-RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages. Br. J. Pharmacol. 2005; 145: 800–10. Urquhart P, Rosignoli G, Cooper D, Motterlini R, Perretti M. Carbon monoxide-releasing molecules modulate leukocyte-endothelial interactions under flow. J. Pharmacol. Exp. Ther. 2007; 321: 656–62. 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: 2243–55. Nakao A, Huang CS, Stolz DB et al. Ex vivo carbon monoxide delivery inhibits intimal hyperplasia in arterialized vein grafts. Cardiovasc. Res. 2011; 89: 457–63. Coeffier M, Le Pessot F, Leplingard A et al. Acute enteral glutamine infusion enhances heme oxygenase-1 expression in human duodenal mucosa. J. Nutr. 2002; 132: 2570–3. Takagi T, Naito Y, Okada H et al. Lansoprazole, a proton pump inhibitor, mediates anti-inflammatory effect in gastric mucosal cells through the induction of heme oxygenase-1 via activation of NF-E2-related factor 2 and oxidation of kelch-like ECH-associating protein 1. J. Pharmacol. Exp. Ther. 2009; 331: 255–64. Alam J, Cook JL. How many transcription factors does it take to turn on the heme oxygenase-1 gene? Am. J. Respir. Cell Mol. Biol. 2007; 36: 166–74. Sun J, Hoshino H, Takaku K et al. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J. 2002; 21: 5216–24. Zhao HD, Zhang F, Shen G et al. Sulforaphane protects liver injury induced by intestinal ischemia reperfusion through Nrf2-ARE pathway. World J. Gastroenterol. 2010; 16: 3002–10.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 46–52 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Therapeutic roles of carbon monoxide
K Katada et al.
38 Mito S, Ozono R, Oshima T et al. Myocardial protection against pressure overload in mice lacking Bach1, a transcriptional repressor of heme oxygenase-1. Hypertension 2008; 51: 1570–7. 39 Harusato A, Naito Y, Takagi Y et al. Inhibition of Bach1 ameliorates indomethacin-induced intestinal injury in mice. J. Physiol. Pharmacol. 2009; 60: 149–54. 40 Granger DN, Richardson PD, Kvietys PR, Mortillaro NA. Intestinal blood flow. Gastroenterology 1980; 78: 837–63. 41 Vollma B, Menger MD. Intestinal ischemia/reperfusion: microcirculatory pathology and functional consequences. Langenbecks Arch. Surg. 2011; 396: 13–29. 42 Haglund U. Gut ischaemia. Gut 1994; 35: S73–6. 43 Hernandez LA, Grisham MB, Twohig B, Arfors KE, Harlan JM, Gramger DN. Role of neutrophils in ischemia-reperfusion-induced microvascular injury. Am. J. Physiol. 1987; 253: H699–703. 44 Kubes P, Hunter J, Granger DN. Ischemia/reperfusion-induced feline intestinal dysfunction: importance of granulocyte recruitment. Gastroenterology 1992; 103: 807–12. 45 Blackwell TS, Yull FE, Chen CL et al. Multiorgan nuclear factor kappa B activation in a transgenic mouse model of systemic inflammation. Am. J. Respir. Crit. Care Med. 2000; 162: 1095–101. 46 Kojima M, Tanabe M, Shinoda M et al. Role of high mobility group box chromosomal protein 1 in ischemia-reperfusion injury in the rat small intestine. J. Surg. Res. 2012; 178: 466–71. 47 Panes J, Perry M, Granger DN. Leukocyte-endothelial cell adhesion: avenues for therapeutic intervention. Br. J. Pharmacol. 1999; 126: 537–50. 48 Chen Y, Lui VC, Rooijen NV, Tam PK. Depletion of intestinal resident macrophages prevents ischaemia reperfusion injury in gut. Gut 2004; 53: 1772–80. 49 Zhang X, Mosser DM. Macrophage activation by endogenous danger signals. J. Pathol. 2008; 214: 161–78. 50 Camhi SL, Alam J, Otterbein L, Sylvester SL, Choi AM. Induction of heme oxygenase-1 gene expression by lipopolysaccharide is mediated by AP-1 activation. Am. J. Respir. Cell Mol. Biol. 1995; 13: 387–98. 51 Shokawa T, Yoshizumi M, Yamamoto H et al. Induction of heme oxygenase-1 inhibits monocyte chemoattractant protein-1 mRNA expression in U937 cells. J. Pharmacol. Sci. 2006; 100: 162–6. 52 Tsoyi K, Nizamutdinova IT, Janq HJ et al. Carbon monoxide from CORM-2 reduces HMGB1 release through regulation of IFN-beta/JAK2/STAT-1/INOS/NO signaling but not COX-2 in TLR-activated macrophages. Shock 2010; 34: 608–14. 53 Srisook K, Han SS, Choi HS et al. CO from enhanced HO activity or from CORM-2 inhibits both O2- and NO production and downregulates HO-1 expression in LPS-stimulated macrophages. Biochem. Pharmacol. 2006; 71: 307–18. 54 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: 239–47. 55 Lee S, Lee SJ, Coronata AA et al. Carbon monoxide confers protection in sepsis by enhancing beclin 1-dependent autophagy and phagocytosis. Antioxid. Redox Signal. 2014; 20: 432–42. 56 Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 2007; 7: 678–89. 57 Hayashi S, Takamiya R, Yamaguchi T et al. Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress: role of bilirubin generated by the enzyme. Circ. Res. 1999; 85: 663–71. 58 Wunder C, Brock RW, McCarter SD et al. Inhibition of haem oxygenase activity increases leukocyte accumulation in the liver
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59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
following limb ischaemia-reperfusion in mice. J. Physiol. 2002; 540: 1013–21. Masini E, Vannacci A, Mastroianni R et al. A carbon monoxide-releasing molecule (CORM-3. abrogates polymorphonuclear granulocyte-induced activation of endothelial cells and mast cells. FASEB J. 2008; 22: 3380–8. Taille C, El-Benna J, Motterlini R. Mitochondrial respiratory chain and NAD(P)H oxidase are targets for the antiproliferative effect of carbon monoxide in human airway smooth muscle. J. Biol. Chem. 2005; 280: 25350–60. Mizuguchi S, Stephen J, Bihari R et al. CORM-3-derived CO modulates polymorphonuclear leukocyte migration across the vascular endothelium by reducing levels of cell surface-bound elastase. Am. J. Physiol. Heart Circ. Physiol. 2009; 297: H920–9. Sheikh SZ, Hegazi RA, Kobayashi T et al. An anti-inflammatory role for carbon monoxide and heme oxygenase-1 in chronic Th2-mediated murine colitis. J. Immunol. 2011; 186: 5506–13. Lee SS, Gao W, Mazzola S et al. Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells. FASEB J. 2007; 21: 3450–7. Soares MP, Seldon MP, Gregoire IP et al. Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation. J. Immunol. 2004; 172: 3553–63. Mizuguchi S, Capretta A, Suehiro S et al. Carbon monoxide-releasing molecule CORM-3 suppresses vascular endothelial cell SOD-1/SOD-2 activity while up-regulating the cell surface levels of SOD-3 in a heparin-dependent manner. Free Radic. Biol. Med. 2010; 49: 1534–41. Zhang X, Shan P, Alam J, Fu XY, Lee PJ. Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3-kinase/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury. J. Biol. Chem. 2005; 280: 8714–21. Song H, Bergstrasser C, Rafat N et al. The carbon monoxide releasing molecule (CORM-3. inhibits expression of vascular cell adhesion molecule-1 and E-selectin independently of haem oxygenase-1 expression. Br. J. Pharmacol. 2009; 157: 769–80. Zabalgoitia M, Colston JT, Reddy SV et al. Carbon monoxide donors or heme oxygenase-1 (HO-1 overexpression blocks interleukin-18-mediated NF-kappaB-PTEN-dependent human cardiac endothelial cell death. Free Radic. Biol. Med. 2008; 44: 284–98. Uchiyama K, Naito Y, Takagi T et al. Carbon monoxide enhance colonic epithelial restitution via FGF15 derived from colonic myofibroblasts. Biochem. Biophys. Res. Commun. 2010; 391: 1122–6. Ahanger AA, Prawez S, Kumar D et al. Wound healing activity of carbon monoxide liberated from CO-releasing molecule (CO-RM). Naunyn Schmiedebergs Arch. Pharmacol. 2011; 384: 93–102. Takagi T, Naito Y, Uchiyama K et al. Carbon monoxide-releasing molecule exerts an anti-inflammatory effect on dextran sulfate sodium-induced colitis in mice. Dig. Dis. Sci. 2011; 56: 1663–71. Nakao A, Kaczorowski DJ, Sugimoto R et al. Application of heme oxygenase-1, carbon monoxide and biliverdin for the prevention of intestinal ischemia/reperfusion injury. J. Clin. Biochem. Nutr. 2008; 42: 78–88. Naito Y, Uchiyama K, Takagi T et al. Therapeutic potential of carbon monoxide (CO) for intestinal inflammation. Curr. Med. Chem. 2012; 19: 70–6. Katada K, Bihari A, Mizuguchi S et al. 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.
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