Digestive Diseases and Sciences

, Volume 57, Issue 6, pp 1496–1503 | Cite as

Gastroprotective Effect of NaHS Against Mucosal Lesions Induced by Ischemia–Reperfusion Injury in Rat

  • Seyyed Ali Mard
  • Niloofar Neisi
  • Ghasem Solgi
  • Maryam Hassanpour
  • Marjan Darbor
  • Maryam Maleki
Original Article

Abstract

Background

Hydrogen sulfide (H2S) has been shown to display anti-inflammatory and antioxidant activities.

Aim

This study was designed to investigate the gastroprotective effect of sodium hydrosulfide (NaHS) on gastric mucosal lesions induced by ischemia–reperfusion (I/R) injury in rats and to determine the possible mechanism involved.

Methods

Fifty-sex male Wistar rats were randomly assigned into sham, control (I/R injury), propargylglycine (PAG)-, l-cysteine-, and NaHS-treated groups. To induce I/R lesions, the celiac artery was first clamped for 30 min (ischemia phase), followed by removal of the clamp artery to allow reperfusion for 3 h. Treated rats received PAG [50 mg/kg, intravenous (i.v.)] or NaHS (160, 320, or 640 ng/kg, i.v.) 5 min before reperfusion. The effect of l-cysteine pretreatment was also investigated. Plasma levels of cytokines and cortisol were measured by an enzyme-linked immunosorbent assay. The gastric tissue samples were collected to quantify the mRNA expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and transforming growth factor (TGF-β) by quantitative real-time PCR.

Results

The total area of gastric lesions significantly decreased following the administration of NaHS and l-cysteine. The highest area of mucosal lesions was observed in PAG-treated rats. The mRNA expression and plasma levels of IL-1β and TNF-α were significantly decreased in l-cysteine- and NaHS-treated rats in a dose-dependent manner. Slightly increased levels of TGF-β were observed in these test groups, but the difference was not statistically significant compared with the other groups. The plasma level of cortisol was also not affected by NaHS treatment.

Conclusion

Our findings indicate that a possible mechanism for the gastroprotective effect of H2S could be through the decreased mRNA expression and plasma release of proinflammatory cytokines.

Keywords

NaHS I/R injury l-cysteine Proinflammatory cytokines Quantitative real-time PCR Rat 

Notes

Acknowledgments

The authors thank the vice-chancellor of research and technology of Ahvaz Jundi Shapour University of Medical Sciences for financial support (grant no. PRC60) and Professor William Winlow (Universities of Central Lancashire and Liverpool) for his comments on the manuscript.

Conflict of interest

None.

References

  1. 1.
    Moore PK, Bhatia M, Moochhala S. Hydrogen sulfide: from the smell of the past to the mediator of the future? Trends Pharmacol Sci. 2003;24:609–611.PubMedCrossRefGoogle Scholar
  2. 2.
    Wang R. Two’s company, three’s a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J. 2002;16:1792–1798.PubMedCrossRefGoogle Scholar
  3. 3.
    Bhatia M. Hydrogen sulfide as a vasodilator. IUBMB Life. 2005;57:603–606.PubMedCrossRefGoogle Scholar
  4. 4.
    Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. EMBO J. 2001;20:6008–6016.PubMedCrossRefGoogle Scholar
  5. 5.
    Kimura H. Hydrogen sulfide as a neuromodulator. Mol Neurobiol. 2002;26:13–19.PubMedCrossRefGoogle Scholar
  6. 6.
    Hosoki R, Matsuki N, Kimura H. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun. 1997;237:527–531.PubMedCrossRefGoogle Scholar
  7. 7.
    Dello Russo C, Tringali G, Ragazzoni E, et al. Evidence that hydrogen sulphide can modulate hypothalamo-pituitary-adrenal axis function: in vitro and in vivo studies in the rat. J Neuroendocrinol. 2000;12:225–233.PubMedCrossRefGoogle Scholar
  8. 8.
    Fiorucci S, Antonelli E, Distrutti E, et al. Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti- inflammatory nonsteroidal drugs. Gastroenterology. 2005;129:1210–1224.PubMedCrossRefGoogle Scholar
  9. 9.
    Zhu XY, Yan XH, Chen SJ. H2S protects myocardium against ischemia/reperfusion injury and its effect on c-Fos protein expression in rats. Sheng Li Xue Bao. 2008;60:221–227.PubMedGoogle Scholar
  10. 10.
    Yonezawa D, Sekiguchi F, Miyamoto M, et al. A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium. Toxicology. 2007;241:11–18.PubMedCrossRefGoogle Scholar
  11. 11.
    Lou LX, Geng B, Du JB, Tang CS. Hydrogen sulphide-induced hypothermia attenuates stress-related ulceration in rats. Clin Exp Pharmacol Physiol. 2008;35:223–228.PubMedGoogle Scholar
  12. 12.
    Wallace JL, Dicay M, McKnight W, Martin GR. Hydrogen sulfide enhances ulcer healing in rats. FASEB J. 2007;21:4070–4076.PubMedCrossRefGoogle Scholar
  13. 13.
    Zanardo RC, Brancaleone V, Distrutti E, Fiorucci S, Cirino G, Wallace JL. Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation. FASEB J. 2006;20:2118–2120.PubMedCrossRefGoogle Scholar
  14. 14.
    Elrod JW, Calvert JW, Morrison J, et al. Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci USA. 2007;104:15560–15565.PubMedCrossRefGoogle Scholar
  15. 15.
    Oh GS, Pae HO, Lee BS, et al. Hydrogen sulfide inhibits nitric oxide production and nuclear factor-B via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Free Radic Biol Med. 2006;41:106–119.PubMedCrossRefGoogle Scholar
  16. 16.
    Mariggio MA, Pettini F, Fumarulo R. Sulfide influence on polymorphonuclear functions: a possible role for Ca2? involvement. Immunopharmacol Immunotoxicol. 1997;19:393–404.PubMedCrossRefGoogle Scholar
  17. 17.
    Mariggio MA, Minunno V, Riccardi S, Santacroce R, De Rinaldis P, Fumarulo R. Sulfide enhancement of PMN apoptosis. Immunopharmacol Immunotoxicol. 1998;20:399–408.PubMedCrossRefGoogle Scholar
  18. 18.
    Hu LF, Wong PT, Moore PK, Bian JS. Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogen-activated protein kinase in microglia. J Neurochem. 2007;100:1121–1128.PubMedCrossRefGoogle Scholar
  19. 19.
    Oates PJ, Hakkinen JP. Studies on the mechanism of ethanol-induced gastric damage in rats. Gastroenterology. 1988;94:10–21.PubMedGoogle Scholar
  20. 20.
    Herskowitz A, Choi S, Ansari AA, Wesselingh S. Cytokine mRNA Expression in post ischemic/reperfusion myocardium. Am J Pathol. 1995;146:419.PubMedGoogle Scholar
  21. 21.
    Andrews FJ, Malcontenti-Wilson C, O’Brien PE. Polymorphonuclear Leukocyte infiltration into gastric mucosa after ischemia-reperfusion. Am J Physiol. 1994;266:G48–G54.PubMedGoogle Scholar
  22. 22.
    Granger DN, Hollwarth ME, Parks DA. Ischemia-reperfusion injury; Role of oxygen-derived free radicals. Acta Physiol Scand Suppl. 1986;548:47–53.PubMedGoogle Scholar
  23. 23.
    Ali ATMM, Al-Swayeh OA, Al-Rashed RS, Al-Mofleh IA, Al-Dhohyan AD, Al-Tuwaijiri AS. Role of oxygen derived free radicals on gastric mucosal injury induced by ischemia-reperfusion. Saudi J Gastroenterol. 1996;2:19–28.PubMedGoogle Scholar
  24. 24.
    Ishii M, Shimizu S, Nawata S, Kiuchi Y, Yamamoto T. Involvement of reactive oxygen species and nitric oxide in gastric ischemia- reperfusion injury in rats: protective effect of tetrahydrobiopterin. Dig Dis Sci. 2000;45:93–98.PubMedCrossRefGoogle Scholar
  25. 25.
    Cybulsky MI, McComb DJ, Movat HZ. Neutrophil leukocyte emigration induced by endotoxin. Mediator roles of interleukin1and Tumor necrosis factor-α. J Immunol. 1988;140:3144–3149.PubMedGoogle Scholar
  26. 26.
    Konturek PC, Duda A, Brzozowski T, et al. Activation of genes for superoxide dismutase, interleukin-1beta, tumor necrosis factor-alpha, and intercellular adhesion molecule-1 during healing of ischemia-reperfusion-induced gastric injury. Scand J Gastroenterol. 2000;35:452–463.PubMedCrossRefGoogle Scholar
  27. 27.
    Hato S, Urakami A, Yamano T, et al. Attenuation of liver and lung injury after hepatic ischemia and reperfusion by a cytokine-suppressive agent, FR167653. Eur Surg Res. 2001;33:202–209.PubMedCrossRefGoogle Scholar
  28. 28.
    El Eter E, Al Tuwaijiri A, Hagar H, Arafa M. In vivo and in vitro antioxidant activity of ghrelin: attenuation of gastric ischemic injury in the rat. J Gastroenterol Hepatol. 2007;22:1791–1799.PubMedCrossRefGoogle Scholar
  29. 29.
    Wada K, Kamisaki Y, Kitano M, Kishimoto Y, Nakamoto K, Itoh T. A new gastric ulcer model induced by ischemia-reperfusion in the rat: role of leukocytes on ulceration in rat stomach. Life Sci. 1996;59:295–301.CrossRefGoogle Scholar
  30. 30.
    Xing L, Karinch AM, Kauffman GL Jr. Mesolimbic expression of neurotensin and neurotensin receptor during stress-induced gastric mucosal injury. Am J Physiol. 1998;274:R38–R45.PubMedGoogle Scholar
  31. 31.
    Wei R, Listwak SJ, Sternberg EM. Lewis hypothalamic cells constitutively and upon stimulation express higher levels of mRNA for pro-inflammatory cytokines and related molecules: comparison with inflammatory resistant Fischer rat hypothalamic cells. J Neuroimmunol. 2003;135:10–28.PubMedCrossRefGoogle Scholar
  32. 32.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–408.PubMedCrossRefGoogle Scholar
  33. 33.
    Xu Z, Prathapasinghe G, Wu N, Hwang SY, Siow YL, O K. Ischemia-reperfusion reduces cystathionine-β-synthase-mediated hydrogen sulfide generation in the kidney. Am J Physiol Renal Physiol. 2009;297:F27–F35.PubMedCrossRefGoogle Scholar
  34. 34.
    Kang K, Zhao M, Jiang H, Tan G, Pan S, Sun X. Role of hydrogen sulfide in hepatic ischemia-reperfusion-induced injury in rats. Liver Transpl. 2009;15:1306–1314.PubMedCrossRefGoogle Scholar
  35. 35.
    Yusuf M, Kwong Huat BT, Hsu A, Whiteman M, Bhatia M, Moore PK. Streptozotocin-induced diabetes in the rat is associated with enhanced tissue hydrogen sulphide biosynthesis. Biochem Biophys Res Commun. 2005;333:1146–1152.PubMedCrossRefGoogle Scholar
  36. 36.
    Bhatia M, Wong FL, Fu D, Lau HY, Moochhala SM, Moore PK. Role of hydrogen sulphide in acute pancreatitis and associated lung injury. FASEB J. 2005;19:623–625.PubMedGoogle Scholar
  37. 37.
    Wang W, Koka V, Lan HY. Transforming growth factor-b and and Smad signalling in kidney diseases. Nephrology (Caltron). 2005;10:48–56.CrossRefGoogle Scholar
  38. 38.
    Ogias D, Bitencourt B, Alvares EP, Gama P. Corticosteroids induce the differential expression of TGF beta isoforms, receptors and signaling in the gastric mucosa of suckling rats. Regul Pept. 2006;135:17–22.PubMedCrossRefGoogle Scholar
  39. 39.
    Linard C, Ropenga A, Vozenin-Brotons MC, Chapel A, Mathe D. Abdominal irradiation increases inflammatory cytokine expression and activates NF-kappa B in rat ileal muscularis layer. Am J Physiol Gastrointest Liver Physiol. 2003;285:G556–G565.PubMedGoogle Scholar
  40. 40.
    Hanada T, Yoshimura A. Regulation of cytokine signaling and inflammation. Cytokine Growth Factor Rev. 2002;13:413–421.PubMedCrossRefGoogle Scholar
  41. 41.
    Yong SJ, Adlakha A, Limper AH. Circulating transforming growth factor-beta (1): a potential marker of disease activity during idiopathic pulmonary fibrosis. Chest. 2001;120:68S–70S.PubMedCrossRefGoogle Scholar
  42. 42.
    Moustakas A, Pardali K, Gaal A, Heldin CH. Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett. 2002;82:85–91.PubMedCrossRefGoogle Scholar
  43. 43.
    Tsigos C, Chrousos GP. Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002;53:865–871.PubMedCrossRefGoogle Scholar
  44. 44.
    Ichikawa H, Yoshida N, Takano H, et al. A novel vitamin E derivative (TMG) protects against gastric mucosal damage induced by ischemia and reperfusion in rats. Dig Dis Sci. 2003;48:54–58.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Seyyed Ali Mard
    • 1
  • Niloofar Neisi
    • 2
  • Ghasem Solgi
    • 3
  • Maryam Hassanpour
    • 1
  • Marjan Darbor
    • 1
  • Maryam Maleki
    • 1
  1. 1.Department of Physiology, Physiology Research Center (PRC), Research institute for infectious diseases of digestive system, School of MedicineAhvaz Jundi Shapur University of Medical SciencesAhvazIran
  2. 2.Research institute for infectious diseases of digestive system and Department of Virology, The school of medicineAhvaz Jundi Shapur University of Medical SciencesAhvazIran
  3. 3.Department of Immunology, School of MedicineHamadan University of Medical Sciences (UMSHA)HamadanIran

Personalised recommendations