Abstract
Nonsteriodal antiinflammatory drugs initiate gastric ulceration and delay gastric ulcer healing. This study aimed to investigate the role of epithelial cell proliferation in delayed ulcer healing and to identify the most reproducible technique for measuring cell proliferation. Rats with acetic acid-induced gastric ulcers were treated for two weeks with indomethacin (1 mg/kg), aspirin (200 mg/kg), or vehicle control. Ulcers were assessed by macroscopic measurement of ulcer area, quantitative histological measurement of mucosal regeneration, and 5-bromo-2′-deoxyuridine immunohistochemistry to assess epithelial cell proliferation. Indomethacin and aspirin significantly delayed ulcer healing and inhibited mucosal regeneration. Three techniques for assessing cell proliferation were compared, and a scoring system, designed to take into account the entire tissue, was shown to be the most reproducible technique. Indomethacin significantly enhanced cell proliferation in the fundic area of ulcer and aspirin had no effect on cell proliferation. We conclude that aspirin and indomethacin delay ulcer healing by an inhibition of mucosal regeneration, but they do not inhibit epithelial cell proliferation.
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Caruso I, Bianchi Porro G: Gastroscopic evaluation of anti-inflammatory agents. Br Med J 280:75–77, 1980
Silvoso GR, Ivey KJ, Butt JH, Lockard OO, Holt SD, Sisk C, Baskin WN, Mackercher PA, Hewett J: Incidence of gastric lesions in patients with rheumatic disease on chronic aspirin therapy. Ann Intern Med 91:517–520, 1979
Lancaster-Smith MJ, Jaderberg ME, Jackson DA: Ranitidine in the treatment of non-steroidal anti-inflammatory drug associated gastric and duodenal ulcers. Gut 32:252–255, 1991
Penney AG, Andrews FJ, O'Brien PE: Effects of misoprostol on delayed ulcer healing by aspirin. Dig Dis Sci 39:934–939, 1994
Ogihara Y, Fuse Y, Okabe S: Effects of indomethacin and prednisolone on connective tissue at the base of acetic acid-induced gastric ulcers in rats.In Mechanisms of Injury, Protection and Repair of the Upper Gastrointestinal Tract. A Garner, PE O'Brien (eds). Chichester, John Wiley & Sons, 1991, pp 455–465
Hirose H, Takeuchi K, Okabe S: Effect of indomethacin on gastric mucosal blood flow around acetic acid-induced gastric ulcers in rats. Gastroenterology 100:1259–1265, 1991
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
Tarnawski A, Stachura J, Douglass TG, Krause WJ, Gergely H, Sarfeh IJ: Indomethacin impairs quality of experimental gastric ulcer healing: A quantitative histological and ultrastructural analysis.In Mechanisms of Injury, Protection and Repair of the Upper Gastrointestinal Tract. A Garner, PE O'Brien (ed.). Chichester, John Wiley & Sons, 1991, pp 521–531
Helander HF: Morphological studies on the margin of gastric corpus wounds in the rat. J Submicrosc Cytol 15:627–643, 1983
Helpap B, Hattori T, Gedigk P: Repair of gastric ulcer. A cell kinetic study. Virchows Arch (Pathol Anat) 392:159–170, 1981
Kuwayama H, Nakajima N, Matsuo Y, Eastwood GL: Effects of single parental indomethacin injection in rat fundic and antral epithelial proliferation. J Clin Gastroenterol 12:S72-S75, 1990
Baumgartner A, Koelz HR, Halter F: Indomethacin and turnover of gastric mucosal cells in the rat. Am J Physiol 250:G830-G835, 1986
Eastwood GL, Quimby GF: Effect of chronic aspirin ingestion on epithelial proliferation in rat fundus, antrum, and duodenum. Gastroenterology 82:852–856, 1982
Kuwayama H, Eastwood GL. Effects of water immersion restraint stress and chronic indomethacin ingestion on gastric antral and fundic epithelial proliferation. Gastroenterology 88:362–365, 1985
Svendson LB, Hart Hansen O, Larsen JK, Johansen A, Stener Jorgensen DF: The effect of acetyl salicylic acid and indomethacin on cell proliferation kinetics in the human gastric mucosa. Scand J Rheumatol 16:107–111, 1987
Uribe A, Rubio C, Johansson C: Alternating proliferative capacity in the rat gastrointestinal mucosa. Effects of E2 prostaglandins and indomethacin. Scand J Gastroenterol 23:163–170, 1988
Uribe A: Indomethacin accelerates clearance of labeled cells and increases DNA synthesis in gastrointestinal mucosa of the rat. Dig Dis Sci 37:403–408, 1992
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
Levi S, Goodlad RA, Lee CY, Stamp G, Walport MJ, Wright NA, Hodgson HJF: Inhibitory effect of non-steroidal anti-inflammatory drugs on mucosal cell proliferation associated with gastric ulcer healing. Lancet 336:840–843, 1990
Schmassmann A, Tarnawski A, Peskar BM, Varga L, Flogerzi B, Halter F: Influence of acid and angiogenesis on kinetics of gastric ulcer healing in rats: Interaction with indomethacin. Am J Physiol 268:G276-G285, 1995
Okabe S, Takeuchi K, Honda K, Takagi K: Effects of acetylsalicylic acid (ASA), ASA plus t-glutamine andl-glutamine on healing of chronic gastric ulcer in the rat. Digestion 14:85–88, 1976
Lacy ER, Kuwayama H, Cowart KS, King JS, Deutz AH, Sistrunk S: A rapid, accurate, immunohistochemical method to label proliferating cells in the digestive tract. A comparison with tritiated thymidine. Gastroenterology 100:259–262, 1991
Guilford JS: Fundamental Statistics in Psychology and Education. Tokyo, McGraw-Hill, 1973, 263 pp
Montandon D, D'Andiran G, Gabbiani G: The mechanism of wound contraction and epithelialization. Clin Plast Surg 4:325–345, 1977
Hase S, Nakazawa S, Tsukamoto Y, Segawa K: Effects of prednisolone and human epidermal growth factor on angiogenesis in granulation tissue of gastric ulcer induced by acetic acid. Digestion 42:135–142, 1989
Uchida M, Kawano O, Misaki N, Irino O: Healing process of acetic acid-induced gastric ulcer and gastric mucosal prostaglandin E generation level in rats. Jpn J Pharmacol 50:366–368, 1989
Garner A: Mechanisms of action of aspirin on the gastric mucosa of the guinea pig. Acta Physiol Scand Special Suppl: 101–110, 1978
Rainsford KD: The effects of aspirin and other non-steriod anti-inflammatory/analgesic drugs on gastro-intestinal mucus glycoprotein biosynthesisin vivo: Relationship to ulcerogenic actions. Biochem Pharmacol 27:877–885, 1978
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This study was supported by a grant from the Alfred Hospital Medical Research Advisory Committee and the National Health and Medical Research Council of Australia.
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Penney, A.G., Malcontenti-Wilson, C., O'Brien, P.E. et al. NSAID-induced delay in gastric ulcer healing is not associated with decreased epithelial cell proliferation in rats. Digest Dis Sci 40, 2684–2693 (1995). https://doi.org/10.1007/BF02220461
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DOI: https://doi.org/10.1007/BF02220461