Hydrogen mediates suppression of colon inflammation induced by dextran sodium sulfate (original) (raw)
Related papers
Molecular hydrogen is comparable to sulfasalazine as a treatment for DSS-induced colitis in mice
2021
Colitis is an inflammatory condition of the bowels associated with abdominal pain, diarrhea, fatigue, and fever. Its etiology is multifactorial but related to the overproduction of inflammatory and oxidative mediators. There is currently no cure for this disease, and drugs used to manage it often have deleterious side effects. H2 is recognized as having anti-inflammatory and antioxidant effects, which may qualify it as a novel therapeutic for colitis. We induced an acute model of colitis in mice by administering dextran sulfate sodium (DSS) in drinking water for seven days. Mice were divided into five groups (n=6); normal, colitis, H2-treated colitis, sulfasalazine-treated colitis, and H2 plus sulfasalazine-treated colitis. From days three to ten, mice were given H2, sulfasalazine, or both. H2 was administered via dissolving a hydrogen-generating tablet in water to make hydrogen-rich water (HRW), which was ingested ad libitum and via oral gavage (200 μL). The Disease Activity Index ...
Digestive Diseases and Sciences, 2011
Background Endogenous hydrogen sulfide (H 2 S) is increasingly being recognized as an important gaseous physiological mediator. Accumulating evidence shows the functions of H 2 S in various models of disease, but rarely in colitis. In this study, we investigated the role of endogenous H 2 S in a dextran sodium sulfate (DSS)-induced colitis model. Methods Acute colitis was induced using 8% DSS in male BALB/c mice. The mRNA expression of cystathionine clyase (CSE), the primary synthetase of H 2 S in the gastrointestinal tract, and cystathionine-b-synthetase (CBS) was measured by real-time RT-PCR. The amount of H 2 S in the colonic mucosa was measured by gas chromatography. Colitis severity was evaluated clinically, histologically, and biochemically under the condition of co-treatment with DLpropargylglycine (PAG), an irreversible CSE inhibitor, and sodium sulfide (Na 2 S), an H 2 S donor. Results The mRNA expression levels of CSE and CBS, and the H 2 S content in the colonic mucosa were increased with time after DSS administration. The disease activity index, which was determined by weight loss, stool consistency, and intestinal bleeding, increased after DSS administration. PAG significantly enhanced the increase in the disease activity index scores. PAG also significantly increased tissue-associated myeloperoxidase activity and thiobarbituric acid-reactive substances in the inflamed mucosa. Moreover, Na 2 S counteracted these effects of PAG.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2014
During a course of colitis, production of the gaseous mediator hydrogen sulfide (H2S) is markedly up-regulated at sites of mucosal damage and contributes significantly to healing and resolution of inflammation. The signaling mechanisms through which H2S promotes resolution of colitis are unknown. We hypothesized that the beneficial effects of H2S in experimental colitis are mediated via stabilization of hypoxia-inducible factor (HIF)-1α. The hapten dinitrobenzene sulfonic acid was used to induce colitis in rats and mice. This resulted in an elevated expression of the H2S-producing enzyme, cystathionine γ-lyase (CSE), and HIF-1α at sites of mucosal ulceration, and the expression of these 2 enzymes followed a similar pattern throughout the course of colitis. This represented a functionally important relationship because the loss of CSE-derived H2S production led to decreased HIF-1α stabilization and exacerbation of colitis. Furthermore, application of an H2S-releasing molecule, dially...
Experimental Ulcerative Colitis Impairs Antioxidant Defense System in Rat Intestine
Digestive Diseases and Sciences - DIGEST DIS SCI, 2000
Increasing attention has been given recently to the role of free radicals in the pathogenesis of ulcerative colitis, since the inflamed intestine is exposed to oxidative stress generated by infiltrating macrophages and neutrophils within the lamina propia. The overall goal of this study was to evaluate whether experimental ulcerative colitis induces significant changes in the antioxidant defense system in an experimental model induced by the intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid. Twenty rats were treated with 80 mg/kg body weight of trinitrobenzenesulfonic acid and 20 with the same volume of 0.9% NaCl. Rats were killed at one and two weeks after treatment to evaluate colon damage by light and electron transmission microscopy. The degree of tissue injury and inflammation was determined by measuring alkaline phosphatase, ?-glutamyltranspeptidase, and myeloperoxidase activities and prostaglandin E2 and leukotriene B4. Glutathione levels and the activity of th...
Hydrogen Sulfide: An Endogenous Mediator of Resolution of Inflammation and Injury
Antioxidants & Redox Signaling, 2012
Significance: Hydrogen sulfide is emerging as an important mediator of many aspects of inflammation, and perhaps most importantly as a factor promoting the resolution of inflammation and repair of injury. Recent Advances: In the gastrointestinal tract, H 2 S has been shown to promote healing of ulcers and the resolution of mucosal inflammation. On the other hand, suppression of endogenous H 2 S synthesis impairs mucosal defense and leads to increased granulocyte infiltration. H 2 S has been exploited in the design of more effective and safe anti-inflammatory drugs. Critical Issues: Enteric bacteria can be a significant source of H 2 S, which could affect mucosal integrity; indeed, luminal H 2 S can serve as an alternative to oxygen as a metabolic substrate for mitochondrial respiration in epithelial cells. Enterocytes and colonocytes thereby represent a ''metabolic barrier'' to the diffusion of bacteria-derived H 2 S into the subepithelial space. A compromise of this barrier could result in modulation of mucosal function and integrity by bacterial H 2 S. Future Directions: Improvements in methods for measurement of H 2 S and development of more selective inhibitors are crucial for gaining a better understanding of the pathophysiological importance of this mediator. Results from animal studies suggest that H 2 S-releasing agents are promising therapeutic agents for many indications, but these compounds need to be assessed in a clinical setting. Antioxid. Redox Signal. 17, 58-67.
Decreased Total Antioxidant Capacity in Plasma, but Not Tissue, in Experimental Colitis
Digestive Diseases and Sciences, 2009
The aim of the present work was to compare colonic mucosa and plasmatic oxidative stress measured concomitantly and with different degrees of injury in rats with colitis induced by trinitrobenzene sulfonic acid. Three groups were studied: control group, colitis group, and colitis exacerbated by diclofenac. Enzymatic markers of colon injury showed enhanced activity in both groups with colitis. The colitis group treated with diclofenac presented higher colonic damage score than the other groups. In both groups with colitis, higher values of tert butyl hydroperoxide-initiated-chemiluminescence and thiobarbituric acid-reactive substances in tissue and decreased total radical-trapping antioxidant potential (TRAP) levels in plasma were found. In conclusion, independently of the degree of colonic mucosa injury and inflammation, oxidative stress in tissue occurs as a consequence of pro-oxidants increase, and is not explained by a reduction of antioxidant defenses. In both conditions, TRAP determination decreases in plasma, but not in tissue.
Frontiers in Immunology
Chronic inflammation contributes to tumor initiation in colitis-associated colorectal cancer (CRC). Indeed, inflammatory bowel disease (IBD) patients show an increased risk of developing CRC. Cancer immune evasion is a major issue in CRC and preclinical and clinical evidence has defined a critical role for myeloid-derived suppressor cells (MDSCs) that contribute to tumor growth and progression by suppressing T-cells and modulating innate immune responses. MDSCs comprise a heterogeneous population of immature myeloid cells that can be distinct in two subtypes: CD11b + Ly6G + Ly6C low with granulocytic phenotype (G-MDSCs) and CD11b + Ly6G − Ly6C high with monocytic phenotype (M-MDSCs). Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule that regulates various physiological and pathophysiological functions. In particular, several studies support its anti-inflammatory activity in experimental colitis and ulcer. However, the role of the H2S pathway in innate immune-mediated IBD has not yet been elucidated. To better define a possible link between MDSCs and H2S pathway in colitis-associated CRC development, we used an innate immune-mediated IBD model induced by infection with the bacterium Helicobacter hepaticus (Hh), closely resembling human IBD. Here, we demonstrated an involvement of MDSCs in colitis development. A significant time-dependent increase of both G-MDSCs and M-MDSCs was observed in the colon and in the spleen of Hh-infected mice. Following, we observed that chronic oral administration of the H2S donor DATS reduced colon inflammation by limiting the recruitment of G-MDSCs in the colon of Hh-infected mice. Thus, we identify the metabolic pathway l-cysteine/H2S as a possible new player in the immunosuppressive mechanism responsible for the MDSCs-promoted colitis-associated cancer development.
Inflammatory bowel diseases, 2015
Microbiota dysbiosis and impaired barrier function are among the most prominent features of inflammatory bowel disease. In the gastrointestinal tract, hydrogen sulfide (H2S) is an important regulator of mucosal homeostasis. We hypothesized that H2S promotes resolution of colonic inflammation through actions on microbiota biofilm and the mucus barrier. We used mice genetically deficient for a key enzyme for H2S production (cystathionine γ-lyase) and pharmacologically inhibited that enzyme during colitis in wild-type mice. We tested the effects of administering an H2S donor (diallyl disulfide) to rodents during hapten-induced colitis. Colonic microbiota biofilm was visualized by fluorescent in situ hybridization, and mucus granules were quantified with periodic acid-alcian blue staining. We exposed human microbiota biofilms and planktonic bacteria to H2S donors ex vivo to determine changes in their growth, viability, and biomass. Intestinal microbiota formed linear biofilms in the col...