Gastroprotective effect of heme-oxygenase 1/biliverdin/CO pathway in ethanol-induced gastric damage in mice

Gomes, Antoniella S.; Gadelha, Gemima G.; Lima, Samara J.; Garcia, Joyce A.; Medeiros, Jand Venes R.; Havt, Alexandre; Lima, Aldo Ângelo Moreira; Ribeiro, Ronaldo de Albuquerque; Brito, Gerly Anne Castro; Cunha, Fernando; Souza, Marcellus H.

doi:10.1016/j.ejphar.2010.05.023

Cited by 51 publications

(39 citation statements)

References 29 publications

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“…In addition, such effects were associated with diminished pro-inflammatory cytokine production and neutrophil infiltration as evident in the histological analysis and MPO activity. These findings are consistent with previous studies in which HO-1 expression along with a concurrent production of its metabolites, CO and BVD, showed anti-inflammatory properties in experimental colitis models (Wang et al, 2001;Paul et al, 2005;Hegazi et al, 2005;Jun et al, 2006) or in ethanol-induced gastric damage (Gomes et al, 2010).…”

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confidence: 82%

Role of the haem oxygenase/carbon monoxide pathway in Clostridium difficile toxin A-induced enteritis in mice

Medeiros

Warren

Freire

et al. 2011

Journal of Medical Microbiology

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Clostridium difficile is the major cause of antibiotic-associated colitis, a disease with significant morbidity and mortality. This study investigated the role of the haem oxygenase-1 (HO-1)/carbon monoxide (CO) pathway in C. difficile toxin A-induced enteritis in mice. The HO substrate haemin, zinc protoporphyrin IX (ZnPP IX), a specific HO-1 inhibitor, dimanganese decacarbonyl (DMDC), a CO donor, or an equivalent volume of their respective vehicles were injected subcutaneously 30 min prior to local challenge with toxin A (25 or 50 mg per ileal loop) or PBS. Intestinal ileal loop weight/length ratios were calculated 3 h later. Ileal tissues were collected for histological analysis and measurement of myeloperoxidase (MPO) activity, tumour necrosis factor alpha (TNF-a) and interleukin-1 beta (IL-1b) production by ELISA and immunohistochemistry for HO-1. Treatment of mice subjected to C. difficile toxin A (TcdA) with haemin or DMDC prevented oedema, mucosal disruption and neutrophil infiltration observed in histological analysis. It also decreased TcdAinduced MPO activity and TNF-a or IL-1b production. In contrast, the specific HO-1 inhibitor (ZnPP IX) exacerbated all these evaluated parameters. TcdA increased HO-1 expression as seen by immunohistochemistry. These results suggest that the HO-1/CO pathway exerts a protective role in TcdA-induced enteritis and that its pharmacological modulation might be important for the management of C. difficile-associated disease. INTRODUCTIONClostridium difficile is the major causative agent of antibiotic-associated diarrhoea. The main C. difficile virulence factors are two large exotoxins, toxin A (TcdA) and toxin B (TcdB), which show substantial sequence similarity and share common structural elements (Pothoulakis et al., 1986). A recent report demonstrated that, instead of TcdA, TcdB is actually the essential virulence factor for the development of C. difficileassociated disease (Lyras et al., 2009). However, by using a gene knockout system to inactivate the toxin genes permanently, Kuehne et al. (2010) found that C. difficile producing either one or both toxins showed cytotoxic activity in vitro that translated directly into virulence in vivo, re-establishing the importance of both toxins in the pathogenesis of C. difficile-associated disease. The mechanism of TcdA-induced enteritis involves toxin binding to enterocyte receptors, which leads to infiltration of the mucosa by neutrophils, degranulation of mast cells and activation of sensory and enteric nerves, resulting in enhanced intestinal secretion and motility (Brito et al., 2002b;Kelly et al., 1994a;Pothoulakis et al., 1998).Haem oxygenase (HO; EC 1.14.99.3) catalyses haem degradation to iron, carbon monoxide (CO) and biliverdin (BVD) (Abraham et al., 1988). Three isozymes have been identified: HO-2 and HO-3, which are constitutive forms (Maines et al., 1986;McCoubrey et al., 1997), and HO-1, which is induced by various stimuli such as haem, haemin, cytokines, mitogens, metals, reactive oxygen species, heat shock, UV ...

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supporting

confidence: 82%

Role of the haem oxygenase/carbon monoxide pathway in Clostridium difficile toxin A-induced enteritis in mice

Medeiros

Warren

Freire

et al. 2011

Journal of Medical Microbiology

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“…Our results suggest that administration of 30 mg·kg −1 (20.0 ± 11.9 nmol·g −1 of tissue) of PLS resulted in a significant decrease in the MDA concentrations in ethanol-induced gastropathy (115.1 ± 7.4 nmol·g −1 of tissue) (Figure 4). Several authors evaluated the effect of different gastroprotective and antioxidants extracts, also had similar results [29–31]. Thus, the mechanism through which PLS exerts gastroprotective effects seems to involve an indirect antioxidant activities and a reduction of the lipid peroxidation induced by ethanol.…”

Section: Resultsmentioning

confidence: 85%

“…It has been suggested that oxygen-derived free radicals (ROS) may contribute to ethanol-induced gastric mucosal lesions [27,28] and deplete the reduced glutathione (GSH) content in stomach tissues [21,27,29]. Our results are in accordance with these reports; ethanol induced a decrease in gastric GSH (298.3 ± 18.2 μg/g tissue) as compared to the saline group (415.0 ± 28.7 μg/g tissue) (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

Sulfated-Polysaccharide Fraction from Red Algae Gracilaria caudata Protects Mice Gut Against Ethanol-Induced Damage

et al. 2011

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The aim of the present study was to investigate the gastroprotective activity of a sulfated-polysaccharide (PLS) fraction extracted from the marine red algae Gracilaria caudata and the mechanism underlying the gastroprotective activity. Male Swiss mice were treated with PLS (3, 10, 30 and 90 mg·kg−1, p.o.), and after 30 min, they were administered 50% ethanol (0.5 mL/25 g−1, p.o.). One hour later, gastric damage was measured using a planimeter. Samples of the stomach tissue were also obtained for histopathological assessment and for assays of glutathione (GSH) and malondialdehyde (MDA). Other groups were pretreated with l-NAME (10 mg·kg−1, i.p.), dl-propargylglycine (PAG, 50 mg·kg−1, p.o.) or glibenclamide (5 mg·kg−1, i.p.). After 1 h, PLS (30 mg·kg−1, p.o.) was administered. After 30 min, ethanol 50% was administered (0.5 mL/25g−1, p.o.), followed by sacrifice after 60 min. PLS prevented-ethanol-induced macroscopic and microscopic gastric injury in a dose-dependent manner. However, treatment with l-NAME or glibenclamide reversed this gastroprotective effect. Administration of propargylglycine did not influence the effect of PLS. Our results suggest that PLS has a protective effect against ethanol-induced gastric damage in mice via activation of the NO/KATP pathway.

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“…The participation of K ATP channels in several models of gastric protection was previously described (37, 38). Other studies reported that glibenclamide pretreatment prevented the protective effects of NaHS and Lawesson's reagent against ethanol (13) and NSAIDs (12) induced macroscopic gastric damage, suggesting an involvement of K ATP channels in H 2 S gastroprotective effects.…”

Section: Discussionmentioning

confidence: 99%

The hydrogen sulfide donor, Lawesson's reagent, prevents alendronate-induced gastric damage in rats

Nicolau

Silva

Damasceno

et al. 2013

Braz J Med Biol Res

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Our objective was to investigate the protective effect of Lawesson's reagent, an H2S donor, against alendronate (ALD)-induced gastric damage in rats. Rats were pretreated with saline or Lawesson's reagent (3, 9, or 27 µmol/kg, po) once daily for 4 days. After 30 min, gastric damage was induced by ALD (30 mg/kg) administration by gavage. On the last day of treatment, the animals were killed 4 h after ALD administration. Gastric lesions were measured using a computer planimetry program, and gastric corpus pieces were assayed for malondialdehyde (MDA), glutathione (GSH), proinflammatory cytokines [tumor necrosis factor (TNF)-α and interleukin (IL)-1β], and myeloperoxidase (MPO). Other groups were pretreated with glibenclamide (5 mg/kg, ip) or with glibenclamide (5 mg/kg, ip)+diazoxide (3 mg/kg, ip). After 1 h, 27 µmol/kg Lawesson's reagent was administered. After 30 min, 30 mg/kg ALD was administered. ALD caused gastric damage (63.35±9.8 mm2); increased levels of TNF-α, IL-1β, and MDA (2311±302.3 pg/mL, 901.9±106.2 pg/mL, 121.1±4.3 nmol/g, respectively); increased MPO activity (26.1±3.8 U/mg); and reduced GSH levels (180.3±21.9 µg/g). ALD also increased cystathionine-γ-lyase immunoreactivity in the gastric mucosa. Pretreatment with Lawesson's reagent (27 µmol/kg) attenuated ALD-mediated gastric damage (15.77±5.3 mm2); reduced TNF-α, IL-1β, and MDA formation (1502±150.2 pg/mL, 632.3±43.4 pg/mL, 78.4±7.6 nmol/g, respectively); lowered MPO activity (11.7±2.8 U/mg); and increased the level of GSH in the gastric tissue (397.9±40.2 µg/g). Glibenclamide alone reversed the gastric protective effect of Lawesson's reagent. However, glibenclamide plus diazoxide did not alter the effects of Lawesson's reagent. Our results suggest that Lawesson's reagent plays a protective role against ALD-induced gastric damage through mechanisms that depend at least in part on activation of ATP-sensitive potassium (KATP) channels.

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Gastroprotective effect of heme-oxygenase 1/biliverdin/CO pathway in ethanol-induced gastric damage in mice

Cited by 51 publications

References 29 publications

Role of the haem oxygenase/carbon monoxide pathway in Clostridium difficile toxin A-induced enteritis in mice

Role of the haem oxygenase/carbon monoxide pathway in Clostridium difficile toxin A-induced enteritis in mice

Sulfated-Polysaccharide Fraction from Red Algae Gracilaria caudata Protects Mice Gut Against Ethanol-Induced Damage

The hydrogen sulfide donor, Lawesson's reagent, prevents alendronate-induced gastric damage in rats

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