Skip to main content

Indomethacin treatment during initial period of acetic acid-induced rat gastric ulcer healing promotes persistent polymorphonuclear cell-infiltration and increases future ulcer recurrence

Possible mediation of prostaglandins

Digestive Diseases and Sciences volume 41, pages 2055–2061 (1996)Cite this article

Abstract

The study was performed to examine whether indomethacin administered during the initial period of acetic acid-induced gastric ulcer healing affects future ulcer recurrence. Gastric ulcers were produced in rats by subserosal injection of acetic acid. Indomethacin (1 mg/kg/day, orally) administered either alone or concomitant with ornoprostil (50µg/kg/day, orally) was started on the fourth day and continued for 56 days. In rats whose ulcer healed at the 90th day after production of ulcer, endoscopy was done every 30 days to examine recurrence of ulcer. Gastric specimens were obtained 10, 30, 60, 90, and 240 days after ulcer production for histology, to quantitate the height of regenerated mucosa, thickness of fibrous tissue, degree of polymorphonuclear cell infiltration, and PAS-positive cells. Cumulative ulcer recurrence rate was significantly higher in rats initially treated with indomethacin than in controls. Increased polymorphonuclear cell infiltration was the major histologic abnormality persisting after cessation of indomethacin. Ornoprostil reversed these abnormalities caused by indomethacin. In conclusion, the administration of indomethacin during the initial period of the ulcer healing promoted persistent polymorphonuclear cell infiltration and increased ulcer recurrence rates, possibly via a prostaglandin-dependent mechanism.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Sharon P, Cohen F, Zifroni A, Karmeli F, Ligumski M, Rachmilewitz D: Prostanoid synthesis by cultured gastric and duodenal mucosa: Possible role in the pathogenesis of duodenal ulcer. Scand J Gastroenterol 18:1045–1049, 1983

    PubMed  Google Scholar 

  2. Konturek SJ, Obtulowicz W, Sito E, Oleksy J, Wilkon S, Kiec-Dembinska A: Distribution of prostaglandins in gastric and duodenal mucosa of healthy subjects and duodenal ulcer patients: Effects of aspirin and paracetamol. Gut 22:283–289, 1981

    PubMed  Google Scholar 

  3. Wright JP, Young GO, Klaff LJ, Weers LA, Price SK, Marks IN: Gastric mucosal prostaglandin E levels in patients with gastric ulcer disease and carcinoma. Gastroenterology 82:263–267, 1982

    PubMed  Google Scholar 

  4. Hiller K, Smith CL, Jewell R, Arthur MJP, Ross G: Duodenal mucosa synthesis of prostaglandins in duodenal ulcer disease. Gut 26:237–240, 1985

    PubMed  Google Scholar 

  5. Arakawa T, Nakamura H, Satoh H, Fukuda T, Sakuma H, Kobayashi K: Deficiency of endogenous prostanoids in gastric and duodenal ulcer diseases. J Gastroenterol Hepatol 3:441–449, 1988

    Google Scholar 

  6. Schlegel W, Wenk K, Dollinger HC, Raptis S: Concentrations of prostaglandin A-, E-, and F-like substances in gastric mucosa of normal subjects and of patients with various gastric diseases. Clin Sci Mol Med 52:255–258, 1977

    PubMed  Google Scholar 

  7. Ligumski M, Sharon P, Karmeli F, Rachmilewitz D: Prostaglandins and pathogenesis of duodenal ulcer: No correlation with the gastric mucosal PGE2 content. Isr J Med Sci 15:171–173, 1979

    PubMed  Google Scholar 

  8. Takagi K, Okabe S, Saziki R: A new method for the production of chronic gastric ulcer in rats and the effect of several drugs on its healing. Jpn J Pharmacol 19:418–426, 1969

    PubMed  Google Scholar 

  9. Uchida M, Kawano O, Misaki N, Saitoh K, Irino O: Healing of acetic acid-induced gastric ulcer and gastric mucosal PGI2 level in rats. Dig Dis Sci 35:80–85, 1990

    PubMed  Google Scholar 

  10. Wang JY, Yamasaki S, Takeuchi K, Okabe S: Delayed healing of acetic acid-induced gastric ulcers in rats by indomethacin. Gastroenterology 96:393–402, 1989

    PubMed  Google Scholar 

  11. Tarnawski A, Stachura J, Douglass TG, Krause WJ, Gergely H, Sarfeh IJ: Indomethacin impairs quality of experimental gastric ulcer healing: a quality histologic and ultrastructural analysis.In Mechanisms of Injury, Protection and Repair of The Upper Gastrointestinal Tract. New York, John Wiley & Sons, 1991, pp 521–531

    Google Scholar 

  12. Whittle BJR: Role of prostaglandins in the defense of the gastric mucosa. Brain Res Bull 5(suppl 1):7–14, 1980

    PubMed  Google Scholar 

  13. Satoh H, Shino A, Murakami I, Asano S, Sato F, Inatomi N: New animal model for gastric ulcer recurrence in the rat: bFGF may play a role in prevention of ulcer recurrence. Gastroenterology 102:A159, 1992

    Google Scholar 

  14. Inauen W, Wyss PA, Kayser S, Baumgartner A, Schurer-Maly CC, Koelz HR, Halter F: Influence of prostaglandins, omeprazole, and indomethacin on healing of experimental gastric ulcers in the rat. Gastroenterology 95:636–641, 1988

    PubMed  Google Scholar 

  15. Szabo S, Folkman J, Vattay P, Morales RE, Pinkus GS, Kato K: Accelerated healing of duodenal ulcers by oral administration of a mutein of basic fibroblast growth factor in rats. Gastroenterology 106:1106–1111, 1994

    PubMed  Google Scholar 

  16. Pan S, Liao CH, Lien GS, Chen SH: Histological maturity of healed duodenal ulcers and ulcer recurrence after treatment with colloidal bismuth subcitrate or cimetidine. Gastroenterology 101:1187–1191, 1991

    PubMed  Google Scholar 

  17. Kobayashi K, Arakawa T, Nakamura H, Chono S, Yamada H, Kamata T, Satoh H, Ono T: Protective action of endogenous prostacyclin (PGI2) and prostaglandin E2 (PGE2) in endoscopic polypectomy-induced human ulcers. Gastroenterol Jpn 17:430–433, 1982

    PubMed  Google Scholar 

  18. Wallace JL, Keehan CM, Granger DN: Gastric ulceration induced by nonsteroidal antiinflammatory drugs is a neutrophil-dependent process. Am J Physiol 259(Gastrointest Liver Physiol 22):G462-G467, 1990

    PubMed  Google Scholar 

  19. Wallace JL, Arfors KE, McKnight W: A monoclonal antibody against the CD18 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in rabbit. Gastroenterology 100:878–883, 1991

    PubMed  Google Scholar 

  20. Higuchi K, Arakawa T, Nakagawa K, Nakamura S, Fukuda T, Kobayashi K: Role of adhesion molecules in gastric mucosal damage caused by indomethacin in rats studied immunohistochemically. Gastroenterology 104:A99, 1993

    Google Scholar 

  21. Tarnawski A, Stachura J, Sarfeh IJ, Sekhon S, Krause WJ, Gregely H: Prostacyclin, endothelial cell growth factor and antacid stimulate angiogenesis in injured gastric mucosa. Gastroenterology 100:A174, 1991

    Google Scholar 

  22. Goodlad RA, Madgwick AJ, Moffatt MR, Levin S, Allen JL, Wright NA: The effects of prostaglandin analogue, misoprostol, on cell proliferation and cell migration in the canine stomach. Digestion 46(suppl 2):182–187, 1990

    PubMed  Google Scholar 

  23. Kainoh M, Imai R, Umetsu T, Hattori M, Nishio S: Prostacyclin and beraprost sodium as suppressors of activated rat polymorphonuclear leukocytes. Biochem Pharmacol 39:477–484, 1990

    PubMed  Google Scholar 

  24. Hogaboam CM, Bissonnette EY, Chin BC, Befus AD, Wallace JL: Prostaglandins inhibit inflammatory mediator release from rat mast cells. Gastroenterology 104:122–129, 1993

    PubMed  Google Scholar 

  25. Arakawa T, Satoh H, Fukuda T, Sakuma H, Shigemoto T, Nakamura H, Kobayashi K: Gastric mucosal resistance and prostanoid levels after cimetidine treatment in rats. Digestion 41:1–8, 1988

    PubMed  Google Scholar 

  26. Arakawa T, Watanabe T, Fukuda T, Yamasaki K, Kobayashi K: Rebamipide, novel prostaglandin inducer, accelerates healing and reduces relapse of acetic acid-induced rat gastric ulcer. Comparison with cimetidine. Dig Dis Sci 40:2469–2471, 1995

    PubMed  Google Scholar 

Download references

Author information

Affiliations

  1. From the Third Department of Internal Medicine and Department of Biosignal Analysis, Osaka City University Medical School, 1-5-7 Asahimachi, Abeno-ku, 545, Osaka, Japan

    Tetsuo Arakawa MD, PhD, Toshio Watanabe MD, PhD, Takashi Fukuda MD, PhD, Kazuhide Higuchi MD, PhD, Osamu Takaishi MD, Katsuya Yamasaki MD, PhD, Kenzo Kobayashi MD, PhD & Andrzej Tarnawski MD, DSc

  2. VA Medical Center, Long Beach and the University of California, Irvine, California

    Tetsuo Arakawa MD, PhD, Toshio Watanabe MD, PhD, Takashi Fukuda MD, PhD, Kazuhide Higuchi MD, PhD, Osamu Takaishi MD, Katsuya Yamasaki MD, PhD, Kenzo Kobayashi MD, PhD & Andrzej Tarnawski MD, DSc

Authors
  1. Tetsuo Arakawa MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshio Watanabe MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takashi Fukuda MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuhide Higuchi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Osamu Takaishi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Katsuya Yamasaki MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kenzo Kobayashi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andrzej Tarnawski MD, DSc
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

The work was supported by The Ministry of Education, Science and Culture of Grant-in-Aid for General Scientific Research 02454236 and by the DVA Medical Research Service.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Arakawa, T., Watanabe, T., Fukuda, T. et al. Indomethacin treatment during initial period of acetic acid-induced rat gastric ulcer healing promotes persistent polymorphonuclear cell-infiltration and increases future ulcer recurrence. Digest Dis Sci 41, 2055–2061 (1996). https://doi.org/10.1007/BF02093610

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02093610

Key words

  • prostaglandins
  • indomethacin
  • quality of ulcer healing
  • recurrence
  • gastric ulcer
  • polymorphonuclear cell