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Digestive Diseases and Sciences

, Volume 51, Issue 2, pp 303–309 | Cite as

Essential Role of Pepsin in Pathogenesis of Acid Reflux Esophagitis in Rats

  • Kenji Nagahama
  • Masanori Yamato
  • Hikaru Nishio
  • Koji Takeuchi
Esophageal, Gastric, and Duodenal Disorders

Abstract

Pepsin, a protease activated by gastric acid, is a component of the refluxate, yet the role of pepsin in the pathogenesis of reflux esophagitis has not been well studied. In the present study, we examined the effect of pepstatin, a specific inhibitor of pepsin, on acid reflux esophagitis. Acid reflux esophagitis was induced in rats by ligating both the pylorus and the forestomach for 3 or 4 hr. Pepstatin, ecabet Na (the anti-ulcer drug), and L-glutamine were administered intragastrically after the ligation. Pepstatin or ecabet Na, given intragastrically, significantly prevented esophageal lesions, even though they did not affect basal acid secretion in pylorus-ligated rats. Pepstatin significantly inhibited pepsin activity in vivo and in vitro, while ecabet Na inhibited this activity in vitro. By contrast, L-glutamine given intragastrically aggravated the lesions in a dose-dependent manner, but even in the presence of L-glutamine the development of esophageal lesions was totally prevented by coadministration of pepstatin or ecabet Na. L-Glutamine increased the pH of gastric contents to approximately 2.0, the optimal pH for the proteolytic activity of pepsin in vitro. In addition, intragastric administration of exogenous pepsin worsened the severity of esophageal damage. These results suggest that pepstatin is highly effective against acid reflux esophagitis, without influencing acid secretion, while L-glutamine aggravated these lesions by increasing the pepsin activity by shifting the intraluminal pH to the optimal pH range for proteolytic action. It is assumed that pepsin plays a major pathogenic role in the development of acid reflux esophagitis.

Key Words

acid reflux esophagitis pepsin pathogenesis L-glutamine rat model 

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References

  1. 1.
    DeMeester TR, Wernly JA, Bryant GH, Little AG, Skinner DB: Clinical and in vitro analysis of determinants of gastroesophageal competence: A study of the principles of antireflux surgery. Am J Surg 137:39–46, 1979CrossRefPubMedGoogle Scholar
  2. 2.
    Hunt RH: Importance of pH control in the management of GERD. Arch Intern Med 159:649–657, 1999CrossRefPubMedGoogle Scholar
  3. 3.
    Meuwissen SGM, Klinkenberg-Knol EC: Treatment of reflux oesophagitis with H2-receptor antagonist. Scand J Gastroenterol 23 (Suppl 146):201–213, 1988Google Scholar
  4. 4.
    Klinkenberg-Knol EC, Jansen JBMJ, Lamers CBHQ, Neils F, Snel P, Meuwissen SGM: Use of omeprazole in the management of reflux oesophagitis resistant to H2-receptor antagonists. Scand J Gastroenterol 24 (Suppl 166):88–93, 1989Google Scholar
  5. 5.
    Inatomi N, Nagaya H, Takami K, Shino A, Satoh H: Effects of a proton pump inhibitor, AG–1749 (lansoprazole), on reflux esophagitis and experimental ulcers in rats. Jpn J Pharmacol 55:437–451, 1991PubMedGoogle Scholar
  6. 6.
    Hirschowitz BI: Pepsin and esophagitis. Yale J Biol Med 72:133–143, 1991Google Scholar
  7. 7.
    Lanas AI, Blas JM, Ortego J, Soria J, Sainz R: Adaptation of esophageal mucosa to acid- and pepsin-induced damage: role of nitric oxide and epidermal growth factor. Dig Dis Sci 42:1003–1012, 1997CrossRefPubMedGoogle Scholar
  8. 8.
    Goldberg HI, Dodds WJ, Gee S, Montgomery C, Zboralske FF: Role of acid and pepsin in acute experimental esophagitis. Gastroenterology 56:223–230, 1969PubMedGoogle Scholar
  9. 9.
    Umezawa H, Aoyagi T, Morishima H, Matsuzaki M, Hamada M, Takeuchi T: Pepstatin, a new pepsin inhibitor produced by actinomycetes. J Antibioti 23:259–262, 1970Google Scholar
  10. 10.
    Kunimoto S, Aoyagi T, Morishima H, Takeuchi T, Umezawa H: Mechanism of inhibition of pepsin by pepstatin J. Antibiot 25:251–255, 1972Google Scholar
  11. 11.
    Okabe S, Takeuchi K, Takata Y, Naganuma T, Takagi K: Effects of L-glutamine on various gastric lesions in rats and guinea pigs. Digestion 14:325–331, 1976PubMedGoogle Scholar
  12. 12.
    Salo JA, Lefto VP, Kivilaakso E: Morphologic alterations in experimental esophagitis: light microscopic and scanning and transmission electron microscopic study. Dig Dis Sci 28:440–448, 1983PubMedGoogle Scholar
  13. 13.
    Nagahama K, Yamato M, Kato S, Takeuchi K: Protective effect of lafutidine, a novel H2-receptor antagonist, on reflux esophagitis in rats through capsaicin-sensitive afferent neurons. J Pharmacol Sci 93:55–61, 2003CrossRefPubMedGoogle Scholar
  14. 14.
    Anson ML: The estimation of pepsin, trypsin, papain and cathepsin with hemoglobin. J Gen Physiol 22:79–89, 1938CrossRefGoogle Scholar
  15. 15.
    Klinkenberg-Knol EC, Nelis F, Dent J, Snel P, Mitchell B, Prichard P, Lloyd D, Havu N, Frame MH, Roman J, Walan A, Group LT: Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology 118:661–669, 2000PubMedGoogle Scholar
  16. 16.
    Onoda Y, Magaribuchi T, Tamaki H: Effect of 12-sulfodehydroabietic acid monosodium salt (TA-2711), a new anti-ulcer agent, on gastric secretion and experimental ulcers in rats. Jpn J Pharmacol 51:65–73, 1989PubMedGoogle Scholar
  17. 17.
    Kinoshita M, Endo M, Yasoshima A, Saito N, Yamasaki K, Chishima S, Narita H. Ecabet sodium, a novel locally-acting anti-ulcer agent, protects the integrity of the gastric mucosal gel layer from pepsin-induced disruption in the rat. Aliment Pharmacol Ther 13:687–694, 1999Google Scholar
  18. 18.
    Okabe S, Takeuchi K, Nakamura K, Takagi K: Pathogenesis of gastric lesions induced by aspirin in the pylorus-ligated rat. Jpn J Pharmacol 24:363–371, 1974PubMedGoogle Scholar
  19. 19.
    Hirschowitz BI: A critical analysis, with appropriate controls of gastric acid and pepsin secretion in clinical esophagitis. Gastroenterology 101:1149–1158, 1991PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Kenji Nagahama
    • 1
  • Masanori Yamato
    • 1
  • Hikaru Nishio
    • 1
  • Koji Takeuchi
    • 1
  1. 1.Department of Pharmacology and Experimental TherapeuticsKyoto Pharmaceutical UniversityKyotoJapan

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