Emerging role of carbon monoxide in regulation of cellular pathways and in the maintenance of gastric mucosal integrity

Pharmacological Research 129 (2018) 56–64

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Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs

Review

Emerging role of carbon monoxide in regulation of cellular pathways and in the maintenance of gastric mucosal integrity Katarzyna Magierowska, Tomasz Brzozowski, Marcin Magierowski ∗ Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland

a r t i c l e

i n f o

Article history: Received 25 October 2017 Received in revised form 12 January 2018 Accepted 18 January 2018 Keywords: Carbon monoxide Heme oxygenase Gastric mucosa Gastrointestinal pharmacology

a b s t r a c t Heme oxygenase (HO) catalyzes the degradation of toxic free heme to the equimolar amounts of biliverdin, Fe2+ and concurrently releases of carbon monoxide (CO). CO is nowadays increasingly recognized as an important signaling molecule throughout the body that is involved in many physiological processes and shows multidirectional biological activity. Recent evidence indicates that CO exhibits the anti-inflammatory, anti-proliferative, anti-apoptotic, anti-aggregatory and vasodilatory properties. The cellular mechanisms underlying the activity of CO involve stimulation of cGMP-dependent signaling pathway and large conductance calcium activated K+ channels, the activation of mitogen-activated protein kinases and the nuclear factor k-light chain-enhancer of activated B cells transcription factor pathway. Stimulation of endogenous CO production by HO inducers or the inhalation of CO or the delivery of this gaseous molecule by novel pharmaceutical agents have been found in experimental animal models to be promising in the future therapy of various diseases. CO appears to act as a significant component of the complex mechanism of gastrointestinal (GI) mucosal defense. This gaseous molecule plays an important role in diabetic gastroparesis, prevention of the upper GI mucosal damage, post-operative ileus and the healing of ulcerative colitis. This review focuses on the better understanding mechanisms through which CO contributes to the mechanism of protection, resistance to injury and ulcer healing. It is becoming apparent that the pleiotropic effect of this molecule may increase clinical applicability of CO donors and their implementation in many pharmacological research areas, pharmaceutical industry and health-care system. © 2018 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

6.

Endogenous carbon monoxide (CO) production by heme oxygenase (HO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Toxicity of exogenous CO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Cellular targets of CO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Pharmacological CO donors and HO inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 HO/CO system in gastric mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 5.1. CO-mediated protection against necrotic gastric damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 5.2. CO prevents alendronate-induced gastric damage formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 5.3. Gastroprotection of CO against NSAIDs-induced gastric damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 5.4. CO and stress-induced gastric lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 5.5. CO/HO and gastric ulcer healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Conclusions and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

1. Endogenous carbon monoxide (CO) production by heme oxygenase (HO) ∗ Corresponding author. E-mail address: [email protected] (M. Magierowski). https://doi.org/10.1016/j.phrs.2018.01.008 1043-6618/© 2018 Elsevier Ltd. All rights reserved.

As demonstrated for the first time in the early 1950 by Torgny Sjöstrand small amounts of CO are continuously produced in

K. Magierowska et al. / Pharmacological Research 129 (2018) 56–64

mammalian tissues [1]. In the late 1960, Tenhunen et al. have discovered microsomal HO enzyme implicating its importance in the heme-dependent CO production [2]. The rate of endogenous CO production in human body is about 16,4 ␮mol/h which corresponds to more than 500 ␮mol CO per day [3–5]. About 86% of the endogenously produced CO arises from heme degradation, however, CO may also derive from heme-independent sources such as lipid peroxidation, autooxidation, photooxidation and cytochrome P450-dependent xenobiotics metabolism [6–8]. Three distant, mammalian isoforms of HO have been described, but only HO-1 and HO-2, encoded by different genes, have been shown to be biologically active [9]. HO-3, sharing approximately 90% sequence identity with HO-2, has exclusively been discovered in rat brain [10,11]. Both, HO enzymes catalyze the ␣-specific oxidative cleavage of the heme ring to yield equimolar amounts of biliverdin, Fe2+ and CO. This reaction requires molecular oxygen, NADPH and NADPH-cytochrome P450 reductase for providing reducing equivalents [12]. The family of HO enzymes is an essential component of the smooth endoplasmic reticulum in spleen, liver and kidney being involved in turnover of Hb released from senescent erythrocytes, regulation of hemeprotein level and the cellular protection against toxic effect of intracellular free heme [13,14]. The HO-1 (32 kDa) isoform, a stress protein also known as heat shock protein-32 (HSP-32), is expressed at undetectable or very low levels in a majority of body tissues, except for spleen where HO-1 is constitutively and highly expressed. However, HO-1 expression may be induced by a wide range of stressful stimuli including oxidative stress, ultraviolet A radiation, bacterial lipopolysaccharide (LPS), heavy metals, pro-inflammatory cytokines, nitric oxide (NO) and its substrate- heme [6,15,16]. The induction of HO-1 is considered to be an adaptive mechanism for maintaining cellular homeostasis. Recent studies have identified nuclear translocation of HO-1 following proteolytic cleavage [17]. Even though nuclear localization of HO-1 has been attributed to reduction of enzyme activity, HO-1 is also involved in the mechanism activation of transcription factors in response to oxidative stress [18]. Human HO-1 deficiency has been associated with the growth retardation, hemolysis, nephritis and early death [19,20]. In contrast to HO-1 enzyme known as an inducible isoform, the HO-2 (36 kDa) is constitutive isoform of enzyme with the highest expression being detected in the brain and testes [14]. The heme catalytic domains, being a sequence of 24 amino acid residues, have been identified in both HO-1 and HO-2 enzymes [21]. However, the HO-2 has possessed of two heme regulatory motifs, which are absent in HO-1 structure. This may suggest additional biological functions of HO-2 despite its role in heme degradation process [10,22,23]. For instance, a significant role of HO-2 against neuronal damage has been demonstrated in HO-2 deficient mice and in vivo models of ischemic injury [24].

2. Toxicity of exogenous CO Since years, CO which is a low-molecular-weight diatomic molecule is also conventionally recognized as poisonous gas produced by partial combustion of carbon-based fuels, including gas, oil, charcoal and wood [25]. Due to its invisibility and odourlessness, CO intoxication can evoke fatal health consequences hence being recognized as a “silent killer”. The first study pioneered by Claude Bernard revealed that CO reversibly binds to hemoglobin (Hb) forming carboxyhemoglobin (COHb) [26]. Formation of COHb affects two major functions of Hb: 1) decreases the O2 carrying capacity of blood and 2) impairs the release of O2 from Hb to the recipient tissues resulting in a hypoxia-induced toxicity [27,28]. Physiological COHb level in the blood ranges from 1% to 3% of total

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Hb in non-smokers [29]. Smoking was reported to increase COHb levels by an average of 5%–10% in one or two pack of cigarettes per day in smokers, respectively [29,30]. COHb level up to 10% remains asymptomatic, whereas toxic signs of CO poisoning appear when COHb level reaches 15% –20% [31]. Symptoms of CO poisoning are subtle and can be easily misdiagnosed resembling, in initial phase, flu-like symptoms such as headache, dizziness, nausea and seizures, hypotension and coma in phase of severe toxicity [32,33]. Non-hypoxic mechanism of action of CO through binding to heme in proteins other than Hb has been also proposed [34]. The binding of CO with other metalloproteins such as myoglobin, NO synthase, soluble guanylyl cyclase (sGC), heme oxygenase (HO), NADPH oxidase, prostaglandin H synthase, peroxidase, cytochrome P450, cytochrome c oxidase cannot be discounted considering lethality of CO [35–40].

3. Cellular targets of CO The cellular mechanism underlying beneficial effects of CO is due to competitive binding of heme altering activity of hemoproteins. Physiological action of CO is thought to involve synthesis of cyclic guanosine monophosphate (cGMP) via activation of soluble guanylyl cyclase (sGC) [41,42]. The binding of CO to the heme domains of sGC results in about 4-fold increase of this enzyme activity [43]. On the other hand, it has been speculated that sGC activation by CO occurs in CO-saturated conditions in amount of gas that exceeded its physiological concentrations [44]. Other heme-containing proteins may also serve as targets for CO, e.g. the interaction of CO with cytochrome P-450, cytochrome c oxidase or iNOS results in the inhibition of enzymatic activity of these proteins [45–47]. Interaction with hemoproteins such us cyclooxygenase (COX)-1 and COX-2 might be another potential mechanism of action of CO [48]. Moreover, heme degradation process starts with the formation of the ferric heme-HO complex. This complex possesses spectral similarities to ferric myoglobin and Hb, therefore HO seems to be another notable target of CO [37,49,50]. Interestingly, it has been reported that, despite of heme catalytic domains, HO-2 contains heme regulatory domains with conserved Cys-Pro motif region. These domains provide additional heme binding sites which are not present in HO-1 structure [10]. It has been shown that CO may regulate many physiological processes at a molecular level, however the exact mechanisms still remain to be explored. CO is a potent vasorelaxant due to activation of calcium (Ca2+ )-dependent potassium (K+ ) channels [51]. The CO-mediated vasorelaxation through Kca stimulation has been attributed to direct binding to extracellular histidines or channelassociated heme moiety [52,53]. CO can activate antiapoptotic genes in nuclear factor kappalight-chain-enhancer of activated B cells (NF-␬B)-dependent manner [54]. This gaseous molecule inhibits mitochondrial cytochrome c oxidase to stimulate the reactive oxygen species (ROS) generation. ROS-induced Act phosphorylation subsequently induces the nuclear translocation of NF-␬B, which regulates the transcription and gene expression [55]. Moreover, CO has been shown to exert anti-inflammatory, anti-apoptotic, and anti-proliferative effects through the activation of p38 mitogen-activated protein kinase (p38MAPK) signaling pathway [56–58]. Heat shock protein 70 and caveolin-1 have been recognized as downstream targets for CO-dependent MAPK p38- mediated responses [59,60]. It has been recently demonstrated that CO facilitates NF-E2-related factor 2 (Nrf2) dissociation from Keap1 and therefore enhances the translocation and nuclear accumulation of Nrf2 [61]. Nrf2 binds to antioxidant response element (ARE) sequence in gene promoter and increases Nrf2-regulated transcription of cytoprotective genes.

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Fig. 1. Mechanisms involved in carbon monoxide (CO) activity. CO derived from heme degradation or released from CORMs possibly acts via activity of soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway and calcium (Ca2+ )-dependent potassium (K+ ) channels causing vasorelaxation. Heme-containing proteins may serve as targets for CO, e.g. the interaction of CO with cytochrome P-450, NADPH oxidase, iNOS, cyclooxygenase (COX)-1 and COX-2 might be another potential mechanism of CO action. CO facilitates NF-E2-related factor 2 (Nrf2) dissociation from Keap1 and therefore enhances the translocation and nuclear accumulation of Nrf2. CO is involved in the regulation of NF-␬B and exerts anti-inflammatory, anti-apoptotic, and anti-proliferative activity by p38 mitogen-activated protein kinase (p38MAPK) signaling pathway.

Taken together, CO is involved in regulation of various cellular pathways including activation of NF-␬B and MAPK. Moreover, the activity of HO-1-derived CO may be regulated by Nrf-2. Additionally, CO is considered as vasoactive molecule acting via stimulation of sGC pathway (Fig. 1). 4. Pharmacological CO donors and HO inhibitors A newly discovered class of compounds, named CO-releasing molecules (CORMs), is capable of liberating CO as gaseous molecule in variety of biological systems, and may serve as pharmacological tools to assess the physiological role of CO under experimental conditions [62]. The manganese decacarbonyl ([Mn2 (CO)10 ]), termed CORM-1, tricarbonyldichlororuthenium(II) dimer ([Ru(CO)3 Cl2 ]2 ), termed CORM-2, both soluble in organic solvents, and tricarbonylchloro(glycinato)ruthenium(II) (CORM-3), soluble in water,

have been identified as CO-releasing carbonyl complexes [62]. Sodium boranocarbonate (Na2 [H3 BCO2 ]), CORM-A1, is a water soluble slow CO releaser with no transition metal in its structure [63]. Administration of CORMs became an alternative to other ways of delivering CO to tissues, derived from CO inhalation, the HO-1 induction or the use of prodrugs including methylene chloride, which releases CO upon hepatic metabolism [64]. On the other hand, a series of metal-free CO-releasing molecules have been recently developed and described as BW-CO-101-121 [65,66]. These pharmacological tool differs regarding half-life for CO release. Interestingly, Steiger et al. have recently invented the oral CO release system (OCORS) as coated tablets which, due to cellulose acetate shell porosity, release therapeutically relevant amounts of CO in controlled manner [67]. Metalloporphyrins such as tin, zinc or chromium protoporphyrin considered as HO inhibitors, are used as pharmacological

K. Magierowska et al. / Pharmacological Research 129 (2018) 56–64

tools relevant to investigate the role of HO in various experimental models of many diseases including atherosclerosis, transplant rejections, acute renal or lung injury, the inflammatory disorders of the GI tract and others [68–71].

5. HO/CO system in gastric mucosa CO-dependent gastroprotection has been recently demonstrated in animal models of various digestive disorders such as ischemia/reperfusion-induced injury of small intestine, toxininduced enteritis, experimental colitis, acute liver failure and acute pancreatitis [72–77]. Furthermore, CO, next to another gaseous molecules H2 S or NO, has been reported as a gastroprotective factor within gastric mucosa but the mechanism of gastroprotective action of this molecule in GI tract has not been fully explained [78–80]. HO-2-like immunoreactivity has been detected in parietal cells of the fundic glands and gastrin cells of the pyloric glands of the antral part of the stomach supporting the evidence on the constitutive production of CO by this organ [81]. Interestingly, CORMs may possess antimicrobial activity because these CO donors were found effective in protection against the colonization of the gastric mucosa by antibiotic resistant strains of Helicobacter pylori (H. pylori) [82]. Particularly, the increased effectiveness of the treatment with CO-releasing CORM-2 over CORM-3 has been observed in H. pylori-infected gastric mucosa. The putative mechanism of action has been attributed to binding of CO to bacterial terminal oxidase and inhibition of bacterial urease activity [82]. Moreover, the upregulation of HO-1 can inhibit the major H. pylori encoding virulence factor, CagA, and its phosphorylation which in turn suppressed the H. pylori-induced IL-8 mRNA expression in gastric epithelial cells exposed to this bug [83,84]. Depletion of interstitial cells of Cajal (ICC) in the gastric mucosa and reduction of Kit protein expression, as a marker of ICC loss, are main cellular abnormalities in gastroparesis, which is defined as motility disorder without mechanical obstruction and is characterized by delayed gastric emptying [85]. Choi et al. and Kashyap et al. revealed the restoration of delayed gastric emptying in diabetic mice to normal rates due to induction of HO-1 activity by hemin and inhalation of low doses of CO (100 ppm for 6 h per day), respectively [86,87]. The inhaled CO increased Kit protein expression in gastric tissue but also reduced serum malonyldialdehyde (MDA) content considered as a marker of gastric lipid peroxidation. It is of interest, that abovementioned effects were induced by CO resulting from HO-1 activity, but not by HO-1 activity itself. Interestingly, these beneficial effects of CO were unchanged after HO-1 inhibition [87]. In another study, the superior effect of HO-1 induction towards recovery of ICC number that has been reduced experimentally in the gastric antrum of diabetic rats has also been confirmed [88].

5.1. CO-mediated protection against necrotic gastric damage The pathogenesis of ethanol-induced gastric damage is complex and may involve a few pathways [89]. Direct deleterious effect of ethanol causes necrosis of surface epithelium that undergoes extensive cellular exfoliation [90]. Additionally, due to contact with ethanol, mucosal mast cells release leukotrienes and histamine which trigger constriction of venules and veins and right afterwards dilation of arteries. In turn, hyperemia, increased capillary pressure and membrane permeability can lead to mucosal edema and subepithelial hemorrhage [89,91]. Recent evidence indicates that CO released from different CO donors afforded gastric protection against ethanol-induced gastric lesions [92,93]

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Gomes et al. have revealed that CO-releasing dimanganese dicarbonyl (DMDC) exerts gastroprotection against gastric lesions induced by intragastric application of 50% ethanol in mice possibly due to the antioxidant properties of this gaseous molecule [91]. In another study the ethanol-induced gastropathy in rats was ameliorated by the administration of CORM-2 releasing CO [93]. In their study, ethanol increased HO-1 mRNA, similarly as originally observed by Gomes et al. but the pretreatment with CORM-2 further elevated mRNA expression of this enzyme but failed to influence the expression of HO-1 and Nrf2 determined at the level of proteins [93]. Moreover, CORM-2 releasing CO decreased mRNA expression for gastric mucosal proinflammatory markers iNOS, IL1␤ and COX-2. It is of interest, that CORM-2 dose-dependently increased COHb concentration in blood and CO content in gastric mucosa [93]. Additionally, combination of CORM-2 with NO synthase inhibitor reduced gastroprotective effect of CO donor in this experimental model [93]. Interestingly, CORM-2 applied in a high dose of 100 mg kg−1 even exacerbated the ethanol-induced gastric damage and decreased gastric blood flow, what confirms that CO is beneficial in gastric mucosa only at particular range of doses [93]. Both studies, by Gomes et al. and Magierowska et al., have indicated the sGC/cGMP intracellular signaling as playing a crucial role in CO-induced gastroprotection against ethanol injury in the stomach [92,93]. 5.2. CO prevents alendronate-induced gastric damage formation Similar as in studies with ethanol administration, the activation of sGC has been considered as a putative cellular mechanism through which CO evokes protection against bisphosphonateinduced gastric damage [94]. In their study the administration of alendronate in a dose 30 mg kg−1 , once daily for 4 days, caused macroscopic and microscopic gastric mucosal lesions and this effect was reversed by CO donor, DMDC, and the HO-1 inducer, hemin. In their study the administration of alendronate similarly to ethanol increased the expression of HO-1 mRNA in gastric tissue [94]. Moreover, that pretreatment with CORM-2 afforded protection of gastric mucosa compromised by mild chronic stress, and concomitantly exposed to alendronate [95]. The mechanism of COmediated protection against alendronate-induced injury involves its anti-inflammatory properties and downregulation of NF-␬B and hypoxia-inducible factor 1␣ (HIF-1␣) expression in gastric mucosa. Moreover, CO donors exerted an inhibitory effect on TNF␣ and IL-1␤ expression of mRNA and protein suggesting that the anti-inflammatory activity of CO released from these donors can contribute to protective effects of this gaseous molecule in gastric mucosa injured by these corrosive agents [94,95]. 5.3. Gastroprotection of CO against NSAIDs-induced gastric damage Non-steroidal anti-inflammatory drugs (NSAIDs) act as inhibitors of COX enzymes activity with a subsequent prostaglandins deficiency [96,97]. There are three theories explaining gastric injury following NSAID administration [98]. PGdependent theory of NSAIDs-induced gastric ulceration implies that suppression of PG formation leads to overproduction of vasoconstrictive leukotrienes and perturbation in gastric microcirculation [99,100]. Another two theories are PG-independent. NSAIDs are weak acids remaining non-ionized in the highly acidic gastric juice. They, as a lipid soluble molecules, can easily diffuse through lipid membrane to neutral environment of gastric cells to cause cellular injury [101,102]. NSAIDs are also known to uncouple mitochondrial oxidative phosphorylation leading, firstly, to the decrease of ATP synthesis following disruption of cellular energy metabolism, the cytotoxic Ca2+ efflux and the

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increased membrane permeability, secondly, to the release of ROS and subsequent lipid peroxidation, all responsible for NSAIDsinduced gastropathy [103,104]. Aburaya et al. have demonstrated, in in vitro and in vivo studies, that p38 MAPK activation and subsequent nuclear accumulation of Nrf2 are responsible for HO-1 upregulation caused by NSAIDs [105]. These findings are corroborative with observation by Uc et al. who observed the protection against indomethacin-induced gastric lesions after HO-1 induction in indomethacin-induced gastric injury model in mice [106]. Interestingly, recent evidence indicates that mitochondrial HO-1 translocation could be considered as a novel cytoprotective mechanism against indomethacin-induced gastric injury [107]. HO-1 protein has been found in mitochondria at 4 h after injury suggesting the role of this enzyme in the mechanism of gastric mucosal repair after damage, however, the mechanism of this phenomenon is not clear. Presumably, HO-1 protects mitochondria indirectly by scavenging cytotoxic free heme accumulated in response to NSAIDs administration [107]. It has been shown that CO released from CORM-2 prevented gastric mucosa against drugs-induced gastric damage such as those caused by aspirin [108]. Interestingly, CORM-2 decreased enzymatic H2 S-biosynthesis pathway activity in gastric mucosa compromised by aspirin suggesting that CO-mediated gastroprotection is H2 S-independent. This protective effect of CORM-2 against aspirin damage and accompanying increase in gastric mucosal blood flow may not involve the activity of afferent sensory neurons, but at least in part, can be mediated by endogenous NO biosynthesis because it can be reversed in L-NNA-dependent manner [109]. CO released from CORM-2 reduced aspirin-induced expression of HIF-1␣ and lipid peroxidation [108,109]. It has been demonstrated that derivatives of NSAIDS releasing other gaseous mediator, H2 S are less gastrotoxic and were shown to be more effective anti-inflammatory agents comparing with their parent drugs [110,111]. Therefore, further studies are needed to confirm in the future the efficacy and safety of newly implemented NSAIDs such us aspirin- or naproxen releasing CO. 5.4. CO and stress-induced gastric lesions Hyperacidity as a consequence of gastric acid secretion disturbance, hypermotility and elevated membrane permeability of gastric cells to H+ ions following deterioration of the microcirculation are major factors responsible for gastric hemorrhagic erosions following stress [112–114]. Water immersion and restraint stress (WRS) is a widely accepted and clinically relevant experimental model for studying local gastric ulcerogenic response to stress [115,116]. Interestingly, an increase in gastric HO-1 expression in response to WRS or cold stress has been observed [117–119]. In the study by Magierowska et al., the CORM-2-mediated protection against WRS-induced gastric damage has been attributed to the release of CO from its chemical donor [119]. Furthermore, the pretreatment with CORM-2 elevated expression of HO-1 mRNA in gastric mucosa possibly responsible for an increase in endogenous CO production observed in CORM-2 pretreated gastric mucosa compromised by WRS. Moreover, the CO content in gastric mucosa and COHb in blood were increased after CORM-2 administration. This study has also revealed that gastroprotective activity of CO donor could be explained by the reduction of inflammation since downregulation of mRNA expression for pro-inflammatory COX2 and iNOS has been observed in gastric mucosa pretreated with CORM-2 and subsequently exposed to WRS [119]. CO involvement in ROS production has been reported in a number of regulatory processes including apoptosis [54,55]. There is convincing evidence that CO-mediated gastroprotection against WRS-induced lesions involves inhibition of lipid peroxidation via maintenance and partial preservation of anti-oxidative

superoxide dismutase (SOD) activity [120]. ROS have been also implicated in the pathogenesis of HCl-induced gastric mucosal injury and the activation of HO-1/Nrf2 system seems to be involved in protection against these acute gastric lesions [121]. On the other hand, CO-releasing CORMs attenuated mitochondriaand/or NADPH oxidase-derived ROS generation induced in vitro by TNF-␣/cycloheximide in mouse small intestinal epithelial cells [122–124]. Moreover, CORM-3 decreased inflammation of intestinal muscularis mucosa induced by postoperative ileus via HO-1 induction leading to mitigation of early oxidative response [125]. Therefore, taken together we conclude that CO can attenuate stress-induced gastric lesions and oxidative intestinal damage due to its anti-oxidative and anti-inflammatory activity [119,126]. 5.5. CO/HO and gastric ulcer healing Gastric ulcer healing is a dynamic and complex process in the course of which we can distinguish four stages [127]. Experimental acetic ulcers model, originally described by Takagi et al. and Okabe et al., may be obtained by serosal application or submucosal injection of small amounts of acetic acid [128,129]. Histologically, the gastric ulcer consists of the margin and the base which both form in ulcer development phase (up to three days after injury). The ulcer margin is composed of epithelial cells due to angiogenesis, while granulation tissue in the ulcer base is formed by cells of connective tissue mainly macrophages, fibroblasts and proliferative endothelial cells [130]. Ulcer healing phase starts after 3–10 day from initial injury and depends upon the proliferation and migration of epithelial cells from the ulcer margin to cover the defect of gastric mucosa, the formation of new vessels (angiogenesis) within the granulation tissue and the process of ulcer base contraction. This process called re-epithelization remains under control of growth factors expressed by epithelial cells and factors releasing locally by regenerating cells. In reconstruction phase, between 20 and 40 days after injury, reconstruction of glands, muscularis mucosae and muscularis propria occurs while in maturation phase differentiation of specialized cells takes place [127]. Guo et al. have described for the first time changes in HO-1 protein expression and activity in the course of gastric ulcer healing. HO-1 protein decreased to undetectable level within 2 h after ulceration but this HO-1 protein expression had increased at 6 h after ulcer induction reaching the highest expression between day 3 and 5 and was elevated until day 15 [131]. Therefore, it has been suggested that CO/HO-1 pathway can promote the resolution of inflammation [131]. Interestingly, Takagi et al. demonstrated that CO-saturated saline enhanced gastric ulcer healing in mice [132]. Moreover, it has been demonstrated that CO released from CORM-2 accelerates healing of gastric ulcers in animal model similarly to another important and gastroprotective gaseous transmitter, H2 S released from NaHS [133,134]. This effect was accompanied by the increase in GBF and increased expression for epidermal growth factor and its receptor. Ulcer healing effect of CORM-2 was dependent on the activity of KATP channels, soluble guanylyl cyclase and nitric oxide biosynthesis [133]. However, ulcer healing effect of CO has been shown to be independent on biosynthesis of H2 S [134]. 6. Conclusions and future perspectives CO, next to H2 S and NO is involved in regulation of many physiological functions and in the maintenance of gastric mucosal integrity [78–80,135,136]. CO released from its pharmacological donors and produced endogenously by the activity of HO prevents gastric mucosa against injury induced by various factors, including stress, NSAIDS, ethanol and bisphosphonates (Table 1). Gastroprotective and ulcer healing activity of this gaseous molecule involves

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Table 1 Role of CO/HO-1 system in various models of gastric mucosa injury. CO has been reported to be involved in the maintenance of gastric mucosal integrity, ulcer healing and gastric chemoprevention. The table summarize the possible mechanisms involved in CO activity within gastric mucosa with appropriate literature reference. Model of gastric mucosa injury

Major mechanisms of CO activity

Publications

Ethanol-induced gastric damage

vasorelaxation, sGC/cGMP activation, PGs synthesis, HO-1/Nrf2 induction, anti-oxidative and anti-inflammatory activity vasorelaxation, sGC/cGMP activation, anti-hypoxic activity, cellular inflammatory pathways downregulation

[92,93]

Alendronate-induced gastric damage NSAIDs-induced gastric damage 䊉 Aspirin 䊉 Indomethacin

[106–109]

Stress-induced gastric damage Acetic acid-induced gastric damage and ulcer healing

Gastric cancer

[94,95]

vasorelaxation, sGC/cGMP activation, anti-inflammatory activity, H2 S-independent gastroprotection, afferent sensor nerves independent mitochondrial HO-1 translocation, p38 MAPK/Nrf2/HO-1pathway induction reduction of inflammation, HO-1 induction, NO-independent gastroprotection modulation of HO-1 expression, acceleration of gastric ulcer healing, the enhancement of GBF, upregulation of EGF expression, anti-inflammatory action, independent on H2 S biosynthesis inhibition of IL-8 expression and endothelial cell proliferation in the tumor

[117–120] [131–134]

[137]

Fig. 2. Possible molecular mechanisms involved in carbon monoxide (CO)-mediated gastroprotection.

regulation of gastric microcirculation via sGC pathway. CO inhibited gastric cancer cells proliferation decreasing IL-8 expression [137]. CO modulates several molecular mechanisms such as MAPK, HIF-1␣, Nrf-2 or NF-␬B pathways and therefore these pathways and factors confirm the anti-inflammatory, anti-hypoxic and antioxidative activities of this gas within gastric mucosa (Fig. 2). It has been demonstrated that both, HO-inducer, hemin and HOinhibitors, zinc mesoporphyrin or zinc protoporphyrin decreased gastric acid secrection and therefore, prevented formation of stressinduced gastric lesions in rats [118,138]. On the other hand, CO released from CORM-2, similarly as H2 S and NO, prevented acid-induced duodenal damage by mechanism involving HCO3 − secretion [139]. Interestingly, this stimulatory effect of CORM-2 realeasing CO was significantly attenuated by indomethacin but not NG -nitro-l-arginine methyl ester [140]. Moreover, the application of CORM-2 increased the mucosal prostaglandin E2 content of the duodenum suggesting that CO generated endogenously or exogenously can stimulate HCO3 − secretion in the duodenum and this effect is mediated, at least in part, by endogenous PGs [140]. Nevertheless, this secretory aspect of CO donors seems to be inter-

esting but requires further studies to deeply investigate possible mechanisms involved in CO/HO-mediated regulation of gastric and duodenal secretion. Taken together, according to recently published data, we conclude that CO released from its pharmacological donors could be involved in gastroprotection and acceleration of the healing of preexisiting gastric ulcers but this beneficial effect of CO requires future studies and a confirmation in clinical trials. Interestingly, involvement of CO in pathophysiology of ischemia/reperfusioninduced gastric damage still remains unexplained. Additionally, because CO similarly to H2 S has been shown to prevent formation of NSAIDs-induced gastric damage, parent drugs combined with this molecule releasing moieties could be considered in the pharmacologic strategy to develop novel less gastrotoxic drugs such as aspirin, naproxen or bisphosphonates.

Conflict of interest The authors declared no conflict of interest.

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