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5-Aminosalicylic Acid Improves Indomethacin-Induced Enteropathy by Inhibiting iNOS Transcription in Rats

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Abstract

Nitric oxide has been implicated in the pathogenic mechanism of inflammatory bowel disease states. We evaluated indomethacin-induced enteropathy in rats, in relation to the expression of the inducible isoform of NO synthase (iNOS) using aminosalicylic acid (5-ASA), its isomer 4-ASA (10 or 50 mg/kg/day, po), and dexamethasone, an iNOS transcription inhibitor (3 mg/kg/day, sc). Enteropathy was induced by indomethacin (7.5 mg/kg/day, sc) for two days and the small intestine was examined for lesions over the next 14 days. Indomethacin-induced small-intestinal ulcer size, mucosal myeloperoxidase activity, iNOS expression and serum nitrite/nitrate levels were maximally increased by day 4 and gradually decreased by day 14. Treatment with 5-ASA, but not 4-ASA, decreased indomethacin-induced ulcer length, myeloperoxidase activity, serum nitrite/nitrate levels and iNOS expression at day 4. Dexamethasone had a greater effect than 5-ASA in reducing myeloperoxidase activity and ulcer length by 26 and 32%, respectively. Dexamethasone also reduced serum nitrate/nitrite and iNOS expression to their basal levels. In conclusion, inhibition of iNOS expression by 5-ASA appears to be associated with diminished intestinal ulceration in indomethacin-induced enteropathy.

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References

  1. Kitagawa H, Takeder F, Kohei H (1990) Effect of endothelium derived relaxing factor on the gastric lesion induced by HCl in rats. J Pharmacol Exp Ther 253:1133–1137

    PubMed  CAS  Google Scholar 

  2. Lopez-Belmonte J, Whittle BJR, Moncada S (1993) The actions of nitric oxide donors in the prevention of induction of injury to the rat gastric mucosa. Br J Pharmacol 108:73–78

    PubMed  CAS  Google Scholar 

  3. Whittle BJR, Lopez-Belmonte J, Moncada S (1992) Nitric oxide mediates rat mucosal vasodilation induced by intragastric capsaicin. Eur J Pharmacol 218:339–341

    Article  PubMed  CAS  Google Scholar 

  4. Podolsky RS, Grabowski M, Milner R, Ritchie WP, Dempsey DT (1994) Capsaicin-induced gastric hyperemia and protection are NO dependent. J Surg Res 57:438–442

    Article  PubMed  CAS  Google Scholar 

  5. Brown KW, Hanson PJ, Whittle BJR (1922) Nitric oxide donors increase mucus gel thickness in rat stomach. Eur J Pharmacol 223:103–104

    Article  Google Scholar 

  6. Holzer P, Lippe IT, Tabrizi AL, Lenard L Jr, Bartho L (1997) Dual excitatory and inhibitory effect on nitric oxide on peristalsis in the guinea pig intestine. J Pharmacol Exp Ther 280:154–161

    PubMed  CAS  Google Scholar 

  7. Lyons CR (1995) The role of nitric oxide in inflammation. Adv Immunol 60:323–371

    PubMed  CAS  Google Scholar 

  8. Grisham MB, Jourd’heuil D, Wink DA (1999) Nitric oxide. I. Physiological chemistry of nitric oxide and its metabolites: Implication in inflammation. Am J Physiol 276:G315–G321

    PubMed  CAS  Google Scholar 

  9. Miller MJS, Sandoval M (1999) Nitric Oxide III. A molecular prelude to inflammation. Am J Physiol 276:G795–G799

    PubMed  CAS  Google Scholar 

  10. Rachmilewitz D, Karmeli F, Okon E, Bursztyn M (1995) Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity. Gut 37:247–255

    Article  PubMed  CAS  Google Scholar 

  11. Nandi J, Parasher G, Frenklakh L, Goodman D, Siddiqui T, Oler A, Levine RA (2000) Expression of inducible nitric oxide synthase (iNOs) in rat intestinal mucosa by indomethacin. Gastroenterology 118:A4290

    Article  Google Scholar 

  12. Kimura H, Miura S, Shigematsu T, Ohkubo N, Tsuzuki Y, Kurose I, Higuchi H, Akiba Y, Hokari R, Hirokawa M, Serizawa H, Ishii H (1997) Increased nitric oxide production and inducible nitric oxide synthase activity in colonic mucosa of patients with active ulcerative colitis and Crohn’s disease. Dig Dis Sci 42:1047–1054

    Article  PubMed  CAS  Google Scholar 

  13. Singer II, Kawka DW, Scott S, Weidner JR, Mumford RA, Riehl TE, Stenson WF (1996) Expression of inducible nitric oxide synthase and nitrotyrosine in colonic epithelium in inflammatory bowel disease. Gastroenterology 111:871–885

    Article  PubMed  CAS  Google Scholar 

  14. Battarbee HD, Grisham MB, Johnson GG, Zavecz JH (1996) Superior mesenteric artery blood flow and indomethacin-induced intestinal injury and inflammation. Am J Physiol 271:(Gastrointest Liver Physiol 34):G605–G612

  15. Robert A (1975) An intestinal disease produced experimentally by prostaglandin deficiency. Gastroenterology 69:1045–1047

    PubMed  CAS  Google Scholar 

  16. Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P (1993) Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci USA 90:7240–7244

    Article  PubMed  CAS  Google Scholar 

  17. Santucci L, Fiorucci S, Giansanti M, Buonori PM, DiMatteo FM, Morelli A (1994) Pentoxifylline prevents indomethacin induced acute mucosal damage in rats: role of tumour necrosis factor alpha. Gut 35:909–915

    Article  PubMed  CAS  Google Scholar 

  18. Bertrand V, Guimbund R, Tulliez M, Mauprivez C, Sogni P, Couturier D, Giroud JP, Chaussade S, Chauvelot-Moachon L (1998) Increase in tumor necrosis factor-α production linked to toxicity of indomethacin in the rat small intestine. Br J Pharmacol 124:1385–1394

    Article  PubMed  CAS  Google Scholar 

  19. Saud B, Nandi J, Ong G, Finocchiaro S, Levine RA (2005) Inhibition of TNF-α improves indomethacin-induced enteropathy in rats by modulating iNOS expression. Dig Dis Sci 50:1677–1683

    Article  PubMed  CAS  Google Scholar 

  20. Parasher G, Frenklakh L, Siddiqui T, Nandi J, Levine RA (2001) Nitric oxide inhibitors ameliorate indomethacin-induced enteropathy in rats. Dig Dis Sci 46:2536–2541

    Article  PubMed  CAS  Google Scholar 

  21. Yang Z, Nandi J, Wang J, Bosco G, Gregory M, Chung C, Xie Y, Yang X, Camporesi EM (2006) Hyperbaric oxygenation ameliorates indomethacin-induced enteropathy in rats by modulating TNF- α and IL-1β production. Dig Dis Sci 51:1426–1433

    Article  PubMed  CAS  Google Scholar 

  22. Kennedy M, Wilson L, Szabo C, Salzman AL (1999) 5-aminosalicylic acid inhibits iNOS transcription in human intestinal epithelial cells. Int J Mol Med 4:437–443

    PubMed  CAS  Google Scholar 

  23. Nandi J, Saud B, Palma DT, Levine RA (2003) 5-aminosalicylic acid (5-ASA) improves indomethacin (INDO)-induced enteropathy by inhibiting iNOS transcription in rats. FASEB J 17:A659

    Google Scholar 

  24. Grisham MB, Benoit JN, Granger DN (1996) Assessment of leukocyte involvement during ischemia and re-perfusion of intestine. Methods Enzymol 186:729–742

    Google Scholar 

  25. Takahashi S, Fujita T, Yamamoto A (2000) Role of cyclooxygenase-2 in Helicobacter pylori-induced gastritis in Mongolian gerbils. Am J Physiol 279:G791–G798

    CAS  Google Scholar 

  26. Wallace JL, Cohen MM (1984) Gastric mucosal protection with chronic mild restraint: Role of endogenous prostaglandins. Am J Physiol 247:G127–G132

    PubMed  CAS  Google Scholar 

  27. Veerabagu MP, Opara EI, Meguid MM, Nandi J, Olar A, Holtzapple PG, Levine RA (1996) Mode of food intake reduction in Lewis rat with indomethacin-induced ulcerative ileitis. Physiol Behav 60:381–387

    Article  PubMed  CAS  Google Scholar 

  28. Chen K, Hirota S, Wasa M, Okada A (1999) Expression of NOS II and its role in experimental small bowel ulceration in rats. Surgery 126:553–561

    PubMed  CAS  Google Scholar 

  29. Tanaka A, Hase S, Miyazawa T, Ohno R, Takeuchi K (2002) Role of cyclooxygenase (COX)-1 and COX-2 inhibition in nonsteroidal anti-inflammatory drug-induced intestinal damage in rats: relation to various pathogenic events. J Pharmacol Exp Ther 303:1248–1254

    Article  PubMed  CAS  Google Scholar 

  30. Konaka A, Nishijima M, Tanaka A, Kunikata T, Kato S, Tekeuchi K (1999) Nitric oxide, superoxide radicals and mast cells in pathogenesis of indomethacin-induced small intestinal lesions in rats. J Physiol Pharmacol 50:25–38

    PubMed  CAS  Google Scholar 

  31. Bjarnasson I, Hayllar J, Mac Pherson AJ, Russel AS (1993) Side effects of nonsteroid antiinflammatory drugs on the small and large intestine in humans. Gastroenterology 104:1832–1847

    Google Scholar 

  32. Yamada T, Deitch E, Specian RD, Perry MA, Sartor RB, Grisham MB (1993) Mechanisms of acute and chronic intestinal inflammation induced by indomethacin. Inflammation 17:641–662

    Article  PubMed  CAS  Google Scholar 

  33. Veerabagu MP, Meguid MM, Olar A, Holtzapple PG, Levine RA (1996) Interavenous nucleosides and nucleotide promote healing of small bowel ulcers in experimental entrocolitis. Dig Dis Sci 41:1452–1457

    Article  PubMed  CAS  Google Scholar 

  34. Whittle BJR, Laszlo F, Evans SM, Moncada S (1995) Induction of nitric oxide synthase and microvascular injury in the rat jejunum provoked by indomethacin. Br J Pharmacol 116:2286–2290

    PubMed  CAS  Google Scholar 

  35. Hori M, Kita M, Torihashi S, Miyamoto S, Ong KJ, Sato K, Ozaki H, Karaki H (2001) Upregulation of iNOS by Cox-2 in muscularis resident macrophage of rat intestine stimulated with LPS. Am J Physiol 280:G930–G938

    CAS  Google Scholar 

  36. Takeuchi K, Yokota A, Tanaka A, Takahira Y (2006) Factors involved in upregulation of inducible nitric oxide synthase in rat small intestine following administration of nonsteroidal anti-inflammatory drugs. Dig Dis Sci 51(7):1250–1259

    Article  PubMed  CAS  Google Scholar 

  37. Kim S, Huri D, Snyder S (2005) Inducible nitric oxide synthase binds, s-nitrosylates, and activates cyclooxygenase-2. Science 310:1966–1970

    Article  PubMed  CAS  Google Scholar 

  38. Wahl C, Liptay S, Adler G, Schmid R (1998) Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. J Clin Invest 101:1163–1174

    Article  PubMed  CAS  Google Scholar 

  39. Crotty B, Rosenberg WMC, Aronson JK, Jewell DP (1992) Inhibition of binding of interferon-gamma to its receptor by salicylates used in inflammatory bowel disease. Gut 33:1353–1357

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA

    Jyotirmoy Nandi, Bipin Saud, J. Michael Zinkievich, David T. Palma & Robert A. Levine

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  1. Jyotirmoy Nandi
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  2. Bipin Saud
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  3. J. Michael Zinkievich
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  4. David T. Palma
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  5. Robert A. Levine
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Correspondence to Jyotirmoy Nandi.

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Nandi, J., Saud, B., Zinkievich, J.M. et al. 5-Aminosalicylic Acid Improves Indomethacin-Induced Enteropathy by Inhibiting iNOS Transcription in Rats. Dig Dis Sci 53, 123–132 (2008). https://doi.org/10.1007/s10620-007-9832-2

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  • DOI: https://doi.org/10.1007/s10620-007-9832-2

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