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Hydrogen Sulphide: An Increasing Need for Scientific Equipoise

2009; Elsevier BV; Volume: 137; Issue: 6 Linguagem: Inglês

10.1053/j.gastro.2009.06.073

1528-0012

J. Calvin Coffey, Neil G. Docherty, P. R. O’Connell,

Asthma and respiratory diseases

We read with interest the recent article by Wallace et al1Wallace J.L. Vong L. McKnight W. et al.Endogenous and exogenous hydrogen sulfide promotes resolution of colitis in rats.Gastroenterology. 2009; 137: 569-578Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar that indicates both endogenous and exogenous hydrogen sulphide (H2S) promote resolution of experimental colitis. Inhibition of H2S synthesis was found to be associated with exacerbation of colitis while the administration of H2S donors led to an improvement. The study provides a platform from which to explore the potential roles of H2S in experimental colitis. H2S is a volatile and highly lipid-soluble gaseous transmitter.2Fiorucci S. Distrutti E. Cirino G. et al.The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver.Gastroenterology. 2006; 131: 259-271Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar At physiologic levels, H2S has homeostatic functions while at supraphysiologic levels it is profoundly toxic.3Wang R. Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter?.FASEB J. 2002; 16: 1792-1798Crossref PubMed Scopus (1555) Google Scholar Colonocytes are particularly well adapted to metabolize H2S; however, cellular responses are overwhelmed at higher concentrations.4Leschelle X. Goubern M. Andriamihaja M. et al.Adaptive metabolic response of human colonic epithelial cells to the adverse effects of the luminal compound sulfide.Biochim Biophys Acta. 2005; 1725: 201-212Crossref PubMed Scopus (149) Google Scholar Wong et al3Wang R. Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter?.FASEB J. 2002; 16: 1792-1798Crossref PubMed Scopus (1555) Google Scholar describe the toxic (as well as physiologic) effects of H2S and emphasize that the concentration gradient between physiologic and toxic effects is small. Babidge et al5Babidge W. Millard S. Roediger W. Sulfides impair short chain fatty acid beta-oxidation at acyl-CoA dehydrogenase level in colonocytes: implications for ulcerative colitis.Mol Cell Biochem. 1998; 181: 117-124Crossref PubMed Scopus (84) Google Scholar describe the potentially deleterious effects of millimolar concentrations of H2S on colonocyte health, demonstrating an inhibitory effect on butyrate oxidation. Schmedes et al6Schmedes A. Nielsen J.N. Hey H. et al.Low S-adenosylmethionine concentrations found in patients with severe inflammatory bowel disease.Clin Chem Lab Med. 2004; 42: 648-653Crossref PubMed Scopus (10) Google Scholar have found reduced levels of s-adenosylmethionine (responsible for H2S detoxification) in patients with severe ulcerative colitis. Attenes-Ramos et al7Attene-Ramos M.S. Wagner E.D. Gaskins H.R. et al.Hydrogen sulfide induces direct radical-associated DNA damage.Mol Cancer Res. 2007; 5: 455-459Crossref PubMed Scopus (197) Google Scholar provide strong evidence that H2S at supraphysiologic concentrations are genotoxic. Wallace et al1Wallace J.L. Vong L. McKnight W. et al.Endogenous and exogenous hydrogen sulfide promotes resolution of colitis in rats.Gastroenterology. 2009; 137: 569-578Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar cite several studies that demonstrate anti-inflammatory properties of H2S at physiologic levels. Zanardo et al8Zanardo R.C. Brancaleone V. Distrutti E. et al.Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation.FASEB J. 2006; 20: 2118-2120Crossref PubMed Scopus (712) Google Scholar used 3 different donors to generate levels within the physiologic range; however, the effects of supraphysiologic H2S concentrations were not determined. Wallace et al1Wallace J.L. Vong L. McKnight W. et al.Endogenous and exogenous hydrogen sulfide promotes resolution of colitis in rats.Gastroenterology. 2009; 137: 569-578Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar question whether luminal H2S concentrations reach the supraphysiologic and therefore potentially toxic levels described. Several human studies have demonstrated toxic levels of H2S within the colonic lumen.2Fiorucci S. Distrutti E. Cirino G. et al.The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver.Gastroenterology. 2006; 131: 259-271Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar, 9Pitcher M.C. Cummings J.H. Hydrogen sulphide: a bacterial toxin in ulcerative colitis?.Gut. 1996; 39: 1-4Crossref PubMed Scopus (216) Google Scholar However, these observations must be interpreted with the important caveat that H2S is a highly volatile and lipid-soluble gas that exists in a bound and unbound form in the colonic lumen. As a result, several groups have acknowledged that accurate measurement of H2S is difficult and likely underestimated.9Pitcher M.C. Cummings J.H. Hydrogen sulphide: a bacterial toxin in ulcerative colitis?.Gut. 1996; 39: 1-4Crossref PubMed Scopus (216) Google Scholar, 10Jorgensen J. Mortensen P.B. Hydrogen sulfide and colonic epithelial metabolism: implications for ulcerative colitis.Digestive diseases and sciences. 2001; 46: 1722-1732Crossref PubMed Scopus (49) Google Scholar Interpretation of data obtained using the trinitrobenzene sulfonic acid model requires caution as this model induces an acute colitis with the morphologic and molecular characteristics of a TH1-driven cellular immune response. Ulcerative colitis involves a TH2-driven immune response characterized by neutrophilic infiltration and immunoglobulin G immune complex formation.11Neurath M.F. Fuss I. Kelsall B.L. et al.Antibodies to interleukin 12 abrogate established experimental colitis in mice.J Exp Med. 1995; 182: 1281-1290Crossref PubMed Scopus (1197) Google Scholar Interestingly, Wallace et al1Wallace J.L. Vong L. McKnight W. et al.Endogenous and exogenous hydrogen sulfide promotes resolution of colitis in rats.Gastroenterology. 2009; 137: 569-578Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar noted no inhibitory effect of H2S on neutrophil infiltration. As the effects of H2S seem to be highly context dependent, their observation raises the possibility that an alternative pattern of results might be obtained in a model more reflective of ulcerative colitis. It would be of value to determine the effects of differing H2S levels based on a more inclusive harvest of samples (ie, at several colonic locations) and to determine the contribution of exogenous bacterial production of H2S. There is considerable evidence that exogenous production of H2S, in particular by sulphate reducing bacteria, contributes significantly to H2S concentrations at the gastrointestinal host/bacterial interface. Studies to date indicate that H2S concentrations and sulphate reducing bacteria counts are concomitantly increased in ulcerative colitis. Wallace et al1Wallace J.L. Vong L. McKnight W. et al.Endogenous and exogenous hydrogen sulfide promotes resolution of colitis in rats.Gastroenterology. 2009; 137: 569-578Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar may well be correct in their view of the role of H2S in experimental colitis; however, we would urge a more inclusive interpretation of the biochemical, metabolic, and clinical data relating toxic (millimolar) and physiologic (micromolar) effects of H2S and colitis in the human setting. Endogenous and Exogenous Hydrogen Sulfide Promotes Resolution of Colitis in RatsGastroenterologyVol. 137Issue 2PreviewHydrogen sulfide (H2S) is an endogenous gaseous mediator of mucosal defense with antiinflammatory effects that promote ulcer healing. The effects of H2S during the pathogenesis of colitis have not been established. We analyzed the contribution of H2S to inflammation and ulceration of the colon in a rat model of colitis. Full-Text PDF ReplyGastroenterologyVol. 137Issue 6PreviewWe thank Drs Coffey, Docherty, and O'Connell for their comments on our recent paper in Gastroenterology that focused on the role of hydrogen sulfide (H2S) in resolution of colitis in rats. With respect to the debate over the contribution of luminal H2S to the pathogenesis of ulcerative colitis (and the associated controversy regarding the concentrations of H2S achieved in the human colon), we attempted, within the space constraints of articles in this journal, to provide a balanced summary of some of the key evidence. Full-Text PDF