Digestive Diseases and Sciences

, Volume 47, Issue 1, pp 38–43

NSAID Gastric Ulceration: Predictive Value of Gastric pH, Mucosal Density of Polymorphonuclear Leukocytes, or Levels of IL-8 or Nitrite

  • Akiko Shiotani
  • Yoshio Yamaoka
  • Hala M. T. El-Zimaity
  • M. Ali Saeed
  • Waqar A. Qureshi
  • David Y. Graham
Article
  • 65 Downloads

Abstract

NSAID use and Helicobacter pylori both cause damage to the gastric mucosa and can cause peptic ulcers. Our aim was to test the relationship between gastric mucosal polymorphonuclear leukocyte (PMN) infiltration and the severity of NSAID-induced gastric injury. H. pylori density, mucosal interleukin-8 (IL-8), and nitrite levels were assessed after receiving placebo and again after receiving 1000 mg of naproxen daily for three days. Histology was graded using a visual analog scale (0–5). IL-8 levels were assayed by ELISA and nitrite levels by Griess reaction. Eleven healthy volunteers with H. pylori infection entered. All had normal-appearing gastric mucosa after placebo. Postnaproxen gastric damage included three with none, one with mild, three with moderate, two with severe, and three were very severe mucosal injury (including one with an ulcer >5 mm). There was an inverse correlation between endoscopic score and the pH of the gastric juice post-therapy (R = −0.77, P = 0.004). There was no significant change in histologic or biochemical parameters from pretreatment levels. And none of the parameters (eg, PMN density) predicted endoscopic outcome. In conclusion, there was no relation between mucosal PMN density and endoscopic mucosa injury. PMN infiltration, while not predictive, may be a surrogate for an H. pylori infection-related increased risk of NSAID ulcers.

nitric oxide interleukin 8 Helicobacter pylori endoscopy inflammation polymorphonuclear leukocytes nonsteroidal antiinflammatory drugs volunteers human 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    Graham DY: Nonsteroidal anti-inflammatory drugs, Helicobacter pylori, and ulcers: Where we stand. Am J Gastroenterol 91:2080–2086, 1996Google Scholar
  2. 2.
    Cullen DJE, Hawkey GM, Greenwood DC, Humphreys H, Shepherd U, Logan RF, et al: Peptic ulcer bleeding in the elderly: Relative roles of Helicobacter pylori and non-steroidal anti-inflammatory drugs. Gut 41:459–462, 1997Google Scholar
  3. 3.
    Chan FK, Sung JJ, Suen R, Lee YT, Wu JC, Leung WK, et al: Does eradication of Helicobacter pylori impair healing of nonsteroidal antiinflammatory drug associated bleeding peptic ulcers? A prospective randomized study. Aliment Pharmacol Ther 12:1201–1205, 1998Google Scholar
  4. 4.
    Wu CY, Poon SK, Chen GH, Chang CS, Yeh HZ: Interaction between Helicobacter pylori and non-steroidal anti-inflammatory drugs in peptic ulcer bleeding. Scand J Gastroenterol 33:234–237, 1999Google Scholar
  5. 5.
    Hawkey CJ, Karrasch JA, Szczepanski L, Walker DG, Barkun A, Swannell AJ, et al: Omeprazole compared with misoprostol for ulcers associated with nonsteroidal anti-inflammatory drugs. Omeprazole versus misoprostol for NSAID-induced ulcer management (OMNIUM) study group. N Engl J Med 338:727–734, 1998Google Scholar
  6. 6.
    Yeomans ND, Tulassay Z, Juhasz L, Racz I, Howard JM, Van Rensburg CJ, et al: A comparison of omeprazole with ranitidine foe ulcers associated with nonstroidal antiinflammatory drugs. Acid suppression trial: Ranitidine versus omeprazole for NSAID-associated ulcer treatment (ASTRONAUT) study group. N Engl J Med 338:719–726, 1998.Google Scholar
  7. 7.
    Hawkey CJ: Personal review: Helicobacter pylori, NSAIDs and cognitive dissonance. Aliment Pharmacol Ther 13:695–702, 1999Google Scholar
  8. 8.
    Aalykke C, Lauristen JM, Hallas J, Reinholdt S, Krogfelt K, Lauristen K: Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidal anti-inflammatory drugs: A case—control study. Gastroenterology 116:1305–1309, 1999Google Scholar
  9. 9.
    Avunduk C, Suliman M, Gang D, Polakowski N, Eastwood GL: Gastroduodenal mucosal prostaglandid generation in patients with Helicobacter pylori before and after treatment with bismuth subsalicylate. Dig Dis Sci 36:431–434, 1991Google Scholar
  10. 10.
    Hudson N, Balsitis M, Filipowicz F, Hawkey CJ: Effect of Helicobacter pylori colonization on gastric mucosal eicosanoid synthesis in patients taking non-steroidal anti-inflammatory drugs. Gut 34:748–751, 1993Google Scholar
  11. 11.
    Fu S, Ramanujam KS, Wong A, Fantry GT, Drachenberg CB, James SP, Meltzer SJ, Wilson KT: Increased expression and cellular localization od inducible nitric oxide synthase and cyclooxygenase 2 in Helicobacter pylori gastritis. Gastroenterology 116:1319–1329, 1999Google Scholar
  12. 12.
    Agrawal NM, Roth S, Graham DY, White RH, Germain B, Brown JA, Stromatt SC: Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-inflammatory druginduced gastric ulcer. A randomized, controlled trial. Ann Intern Med 115:195–200, 1991Google Scholar
  13. 13.
    Graham DY: Prevention of gastroduodenal injury induced by chronic nonsteroidal antiinflammatory drug therapy. Gastroenterology 96:675–681, 1989Google Scholar
  14. 14.
    Taha AS, Dahill S, Morran C, Hudson N, Hawkey CJ, Lee FD, Sturrock RD, Russell RI: Neutrophils, Helicobacter pylori, and nonsteroidal anti-inflammatory drug ulcers. Gastoenterology 116:254–258, 1999Google Scholar
  15. 15.
    Crabtree JE, Wyatt JI, Trejdosiewicz LK, Peichl P, Nichols PH, Ramsay N, Primrose JN, Lindley IJD: Interleukin-8 expression in Helicobacter pylori infected, normal, and neoplastic gastroduodenal mucosa. J Clin Pathol 46:61–66, 1994Google Scholar
  16. 16.
    Crabtree JE, Covacci A, Farmery SM, Xiang Z, Tompkins DS, Perry S, Lindley IJ, Rappuoli R: Helicobacter pylori induced interleukin-8 expression in gastric epithelial cells is associated with Cag A positive phenotype. J Clin Pathol 48:41–45, 1995Google Scholar
  17. 17.
    Yamaoka Y, Kita M, Kodama T, Sawai N, Tanahashi T, Kashima K, Imanishi J: Chemokines in the gastric mucosa in Helicobacter pylori infection. Gut 42:609–617, 1998Google Scholar
  18. 18.
    Yamaoka Y, Kodama T, Kita M, Imanishi J, Kashima K, Graham DY: Relation between clinical presentation, Helicobacter pylori density, interleukin 1βand 8 production, and cagA status. Gut 45:804–811, 1999Google Scholar
  19. 19.
    Yamaoka Y, Kita M, Kodama T, Sawai N, Kashima K, Imanishi J: Induction of various cytokines and development of severe mucosal inflammation by cagA gene positive Helicobacter pylori strains. Gut 41:442–451, 1997Google Scholar
  20. 20.
    Kugler P, Drenckhahn D: Intrinsic source of stomach NO. Nature 370:25–26, 1994Google Scholar
  21. 21.
    Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142, 1991Google Scholar
  22. 22.
    Stark ME, Szurszewski JH: Role of nitric oxide in gastrointestinal and hepatic function and disease. Gastroenterology 103:1928–1949, 1992Google Scholar
  23. 23.
    MacNaughton WK, Cirino G, Wallace JL: Endotheliumderived relaxing factor (nitric oxide) has protective actions in the stomach. Life Sci 45:1869–1876, 1989Google Scholar
  24. 24.
    Elliott SN, Mcknight W, Cirino G, Wallance JL: A nitric oxide-releasing nonsteroidal antiinflammatory drug accelerates gastric ulcer healing in rats. Gastroenterology 109:524–530, 1995Google Scholar
  25. 25.
    Wallace JL, Mcknight W, Del Soldato P, Baydoun AR, Cirino G: Anti-thrombotic effects of a nitric oxide-releasing, gastricsparing aspirin derivative. J Clin Invest 96:2711–2718, 1995Google Scholar
  26. 26.
    Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P: Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci USA 90:7240–7244, 1993Google Scholar
  27. 27.
    Shiotani A, Yanaoka K, Iguchi M, Saika A, Itoh H, Nishioka S: Helicobacter pylori infection reduces intraluminal nitric oxide in humans. J Gastroenterol 34:668–674, 1999Google Scholar
  28. 28.
    Iguchi M, Shiotani A, Nishioka S: Helicobacter pylori-infection reduces intraluminal nitric oxide. Scand J Gastroenterol 35:694–698, 2000Google Scholar
  29. 29.
    El-Zimaity HMT, Graham DY, Al-Assi MT, Malaty H, Karttunen TJ, Graham DP, Huberman RM, Genta RM: Interobserver variation in the histopathological assessment of Helicobacter pylori gastritis. Hum Pathol 27:35–41, 1996Google Scholar
  30. 30.
    Graham DY, Malaty HM: Alendronate gastric ulcers. Aliment Pharmacol Ther 13:515–519, 1999Google Scholar
  31. 31.
    Lanza FL, Graham DY, Davis RE, Rack MF: Endoscopic comparison of cimetidine and sucralfate for prevention of naproxen-induced acute gastroduodenal injury. Effect of scoring method. Dig Dis Sci 35:1494–1499, 1990Google Scholar
  32. 32.
    Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 340:1888–1899, 1999Google Scholar
  33. 33.
    Singh G, Triadafilopoulos G: Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol 56(suppl 26):18–24, 1999Google Scholar
  34. 34.
    Langman MJ Weil J, Wainwright P, Lawson DH, Rawlins MD, Logan RF, Murphy M, Vessey MP, Colin-Jones DG: Risks of bleeding peptic ulcer associated with individual nonsteroidal anti-inflammatory drugs. Lancet 343:1075–1078, 1994Google Scholar
  35. 35.
    Garcia Rodriguez LA, Jick H: Risk of upper gastrointestinal bleeding and perforation associated with individual nonsteroidal anti-inflammatory drugs. Lancet 343:769–772, 1994Google Scholar
  36. 36.
    Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM: Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: A randomized, doubleblind, placebo-controlled trial. Ann Intern Med 123:241–249, 1995Google Scholar
  37. 37.
    Needleman P, Isakson PC: The discovery and function of COX-2. J Rheumatol 24(suppl 49):6–8, 1997Google Scholar
  38. 38.
    Masferrer JL, Seibert K, Zweifel B, Needleman P: Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme. Proc Natl Acad Sci USA 89:3817–3921, 1992Google Scholar
  39. 39.
    Crofford LJ: COX-1 and COX-2 tissue expression: Implications and predictions. J Rheumatol 24(suppl 49):15–19, 1997Google Scholar
  40. 40.
    Vane J: Towards a better aspirin. Nature 367:215–216, 1994Google Scholar
  41. 41.
    Schoen RT, Vender RJ: Mechanisms of nonsteroidal antiinflammatory drug-induced gastric damage. Am J Med 86:449–458, 1989Google Scholar
  42. 42.
    Laine L, Sloane R, Ferretti M, Cominelli F: A randomized double-blind comparison of placebo, etodolac, and naproxen on gastrointestinal injury and prostaglandin production. Gastrointest Endosc 42:428–433, 1995Google Scholar
  43. 43.
    Whittle BJR: Mechanisms underlying gastric mucosal damage induced by indomethacin and bile salts, and the actions of prostaglandins. Br J Pharmacol 60:455–460, 1977Google Scholar
  44. 44.
    Wolfe MM, Soll AH: The physiology of gastric acid secretion. N Engl J Med 319:1707–1715, 1988Google Scholar
  45. 45.
    Rees RC: Cytokines as biological response modifiers. J Clin Pathol 45:93–98, 1993Google Scholar
  46. 46.
    Hamlet A, Lindholm C, Nillson O, Olbe L: Aspirin-induced gastritis, like Helicobacter pylori-induced gastritis, disinhibits acid secretion in human: Relation to cytokine expression. Scand J Gastroenterol 33:346–356, 1998Google Scholar
  47. 47.
    Wallace JL: Non-steroidal anti-inflammatory drug gastropathy and cytoprotection: Pathogenesis and mechanisms reexamined. Scand J Gastroenterol 192:3–8, 1992Google Scholar
  48. 48.
    Lipscomb GR, Wallis N, Armstrong G, Goodman MJ, Rees WDW: Influence of Helicobacter pylori on gastric mucosal adaptation to naproxen in man. Dig Dis Sci 41:1583–1588, 1996.Google Scholar
  49. 49.
    Laine L, Cominelli F, Sloane R, Casini-Raggi V, Marin-Sorensen M, Weinstein WM: Interaction of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production: A controlled double-blind trial. Aliment Pharmacol Ther 9:127–135, 1995Google Scholar
  50. 50.
    Macdonald WC: Correlation of mucosal histology and aspirin intake in chronic gastric ulcer. Gastroenterology 65:381–389, 1973Google Scholar
  51. 51.
    Goggin PM, Collins DA, Jazrawi RP, Jackson PA, Corbishley CM, Bourke BE, Northfield TC: Prevalence of Helicobacter pylori infection and its effect on symptoms and nonsteroidal anti-inflammatory drug induced gastrointestinal damage in patients with rheumatoid arthritis. Gut 34:1677–1680, 1993Google Scholar
  52. 52.
    Peterson WL, Lee E, Feldman M: Relationship between Campylobacter pylori and gastritis in healthy humans after administration of placebo or indomethacin. Gastroenterology 95:1185–1197, 1988Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • Akiko Shiotani
    • 1
    • 2
  • Yoshio Yamaoka
    • 1
    • 2
  • Hala M. T. El-Zimaity
    • 1
    • 2
  • M. Ali Saeed
    • 1
    • 2
  • Waqar A. Qureshi
    • 1
    • 2
  • David Y. Graham
    • 1
    • 2
  1. 1.Department of MedicineVA Medical CenterHoustonUSA
  2. 2.Baylor College of MedicineHoustonUSA

Personalised recommendations