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Effects of FK506, an immunosuppressive agent, on genesis of water-immersion stress-induced gastric lesions in rats

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Abstract

We examined the effects of FK506, an immunosuppressive agent, on the genesis of water immersion stress-induced gastric lesions in rats. Using high-performance liquid chromatography, four kinds of prostaglandins, ie, 6-keto-prostaglandin F1α, prostaglandin F2α, prostaglandin E2, and prostaglandin D2, were detected, and no leukotrienes were detected in gastric mucosa in rats without stress. After 6 hr of stress, gastric lesions developed with decreases in all prostaglandin contents, and the emergence of peptide leukotrienes was observed. Intramuscular administration of FK506 (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) reduced lesion index dose-dependently. Administration of FK506 at doses over 0.25 mg/kg decreased all prostaglandin contents, but did not affect the increase in leukotriene contents. Pretreatment with famotidine or omeprazole reduced lesion index, and the protective effects were equivalent to those of 1.0 mg/kg of FK506, although FK506 did not affect gastric secretion during water-immersion stress. Water-immersion stress did not change the activities of xanthine oxidase in either stomach or serum. Polyoxyethylenemodified superoxide dismutase did not prevent gastric lesions. Water-immersion stress significantly increased myeloperoxidase activity in gastric mucosa, and FK506 reduced the increase in myeloperoxidase activity induced by stress. From our results, other factors besides gastric acid secretion and tissue eicosanoid contents, such as chemoattractant factor, might also be involved in the genesis of water-immersion stress-induced gastric lesions in rats.

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References

  1. Takagi K, Okabe S: The effects of drugs on the production and recovery processes of the stress ulcer. Jpn J Pharmacol 18:9–18, 1968

    Google Scholar 

  2. Hayase M, Takeuchi K: Gastric acid secretion and lesion formation in rats under water-immersion stress. Dig Dis Sci 31:166–171, 1986

    Google Scholar 

  3. Takano K, Sugiyama S, Nakazawa S, Ozawa T: The role of phospholipase in the genesis of gastric ulcers in rats. Scand J Gastroenterol 22:577–584, 1987

    Google Scholar 

  4. Kuroiwa M, Sugiyama S, Ohara A, Goto H, Tsukamoto Y, Nakazawa S, Ozawa T: Relationship between gastric mucosal prostaglandin levels and healing of gastric lesions in rats. Clin Exp Pharmacol Physiol 17:755–762, 1990

    Google Scholar 

  5. Kuroiwa M, Sugiyama S, Goto H, Tsukamoto Y, Nakazawa S, Ozawa T: The role of mucosal prostaglandin levels in healing of water immersion-induced gastric ulcers in rats. Scand J Gastroenterol 25:59–65, 1990

    Google Scholar 

  6. Ohara A, Sugiyama S, Kuroiwa M, Goto H, Tsukamoto Y, Ozawa T: Role of leukotrienes in the genesis and healing of water immersion stress-induced gastric ulcers in rats. Biochem Int 23:1055–1062, 1991

    Google Scholar 

  7. Yoshikawa T, Miyagawa H, Yoshida N, Sugino S, Kondo M: Increase in lipid peroxidation in rat gastric mucosal lesions induced by water-immersion restraint stress. J Clin Biochem Nutr 1:271–277, 1986

    Google Scholar 

  8. Garrick T, Leung FW, Buack S, Hirabayashi K, Guth PH: Gastric motility is stimulated but overall blood flow is unaffected during cold restraint in the rat. Gastroenterology 91:141–148, 1986

    Google Scholar 

  9. Murakami M, Lam SK, Inada M, Miyake T: Pathophysiology and pathogenesis of acute gastric mucosal lesions after hypothermic restraint stress in rats. Gastroenterology 88:660–665, 1985

    Google Scholar 

  10. Uehara A, Okumura T, Kitamori S, Takasugi Y, Namiki M: Interleukin-1: A cytokine that has potent antisecretory and anti-ulcer actions via the central nervous system. Biochem Biophys Res Commun 173:585–590, 1990

    Google Scholar 

  11. Wallace JL, Keenan CM, Mugridge KG, Parente L: Reduction of the severity of experimental gastric and duodenal ulceration by interleukin-1β. Eur J Pharmacol 186:279–284, 1990

    Google Scholar 

  12. Robert A, Olafsson AS, Lancaster C, Zhang W: Interleukin-1 is cytoprotective, antisecretory, stimulates PGE2 synthesis by the stomach, and retards gastric emptying. Life Sci 48:123–134, 1991

    Google Scholar 

  13. Okumura T, Uehara A, Kitamori S, Okamura K, Takasugi Y, Namiki M: Prevention by interleukin-1 of intracisternally injected thyrotropin-releasing hormone (TRH) -induced gastric mucosal lesions in rats. Neurosci Lett 125:31–33, 1991

    Google Scholar 

  14. Allam BF, Tillman JE, Thomson TJ, Crossling FT, Gilbert LM: Effective intravenous cyclosporin therapy in a patient with severe Crohn's disease on parenteral nutrition. Gut 28:1166–1169, 1987

    Google Scholar 

  15. Lichtiger S, Present DH: Preliminary report: Cyclosporin in treatment of severe active ulcerative colitis. Lancet 336:16–19, 1990

    Google Scholar 

  16. Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H: FK-506, a novel immunosuppressant isolated from astreptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 40:1249–1255, 1987

    Google Scholar 

  17. Kino T, Hatanaka H, Miyata S, Inamura N, Nishiyama M, Yajima T, Goto T, Okuhara M, Kohsaka M, Aoki H, Ochiai T: FK-506, a novel immunosuppressant isolated from aStreptomyces. II. Immunosuppressive effect of FK-506in vitro. J Antibiot (Tokyo) 40:1256–1265, 1987

    Google Scholar 

  18. Starzl TE, Todo S, Tzakis AG, Gordon RD, Makowka L, Stieber A, Podesta L, Yanaga K, Concepcion W, Iwatsuki S: Liver transplantation: An unfinished product. Transplant Proc 21:2197–2200, 1989

    Google Scholar 

  19. Markus PM, Cai X, Ming W, Demetris AJ, Fung JJ, Starzl TE: Prevention of graft-versus-host disease following allogeneic bone marrow transplantation in rats using FK506. Transplantation 52:590–594, 1991

    Google Scholar 

  20. Siekierka JJ, Hung SHY, Poe M, Lin CS, Sigal NH: A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature 341:755–757, 1989

    Google Scholar 

  21. Tocci MJ, Matkovich DA, Collier KA, Kwok P, Dumont F, Lin S, Degudicibus S, Siekierka JJ, Chin J, Hutchinson NI: The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol 143:718–726, 1989

    Google Scholar 

  22. Brabletz T, Pietrowski I, Serfling E: The immunosuppressive FK506 and cyclosporin A inhibit the generation of protein factors binding to the two purine boxes of the interleukin 2 enhancer. Nucleic Acids Res 19:61–67, 1991

    Google Scholar 

  23. Stevens C, Lempert N, Freed BM: The effects of immunosuppressive agents on in vitro production of human immunoglobulins. Transplantation 51:1240–1244, 1991

    Google Scholar 

  24. Kubes P, Hunter J, Granger DN: Effects of cyclosporin A and FK506 on ischemia-reperfusion-induced neutrophil infiltration in the cat. Dig Dis Sci 36:1469–1472, 1991

    Google Scholar 

  25. Goto H, Nakazawa S, Ozawa T: Decreased levels of prostaglandins I2 and E2 in acute gastric mucosal lesions induced by hypoxia. Biochem Int 14:311–317, 1987

    Google Scholar 

  26. Osada T, Goto H, Tsukamoto Y, Nakazawa S, Sugiyama S, Ozawa T: Role of leukotrienes in hydrochloric acid-induced gastric lesions in rats. Dig Dis Sci 35:186–192, 1990

    Google Scholar 

  27. Akaike T, Ando M, Oda T, Doi T, Ijiri S, Araki S, Maeda H: Dependence on O −2 generation by xanthine oxidase of pathogenesis of influenza virus infection in mice. J Clin Invest 85:739–745, 1990

    Google Scholar 

  28. Rodell TC, Cheronis JC, Ohnemus CL, Piermattei DJ, Repine JE: Xanthine oxidase mediates elastase-induced injury to isolated lungs and endothelium. J Appl Physiol 63:2159–2163, 1987

    Google Scholar 

  29. Krawisz JE, Sharon P, Stenson WF: Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Gastroenterology 87:1344–1350, 1984

    Google Scholar 

  30. Anson ML, Mirsky AE: The estimation of pepsin with hemoglobin. J Gen Physiol 16:59–63, 1933

    Google Scholar 

  31. Shay H: Etiology of peptic ulcer. Am J Dig Dis 6:29–43, 1961

    Google Scholar 

  32. Levy M: Aspirin use in patients with major upper gastroin-testinal bleeding and peptic-ulcer disease. N Engl J Med 290:1158–1162, 1974

    Google Scholar 

  33. Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (London) New Biol 231:232–235, 1971

    Google Scholar 

  34. Hawkey CJ, Walt RP: Prostaglandins for peptic ulcer. Lancet 2:1084–1086, 1986

    Google Scholar 

  35. Granger DN, Rutili G, McCord JM: Superoxide radicals in feline intestinal ischemia. Gastroenterology 81:22–29, 1981

    Google Scholar 

  36. Smith SM, Grisham MB, Manci EA, Granger DN, Kvietys PR, Russell JM: Gastric mucosal injury in the rat. Gastroenterology 92:950–956, 1987

    Google Scholar 

  37. Naito Y, Yoshikawa T, Ando T, Kishi A, Ueda S, Oyamada H, Kondo M: Changes in superoxide dismutase activity in the gastric mucosa of peptic ulcer patients. J Clin Gastroenterol 14(suppl 1):S131–S134, 1992

    Google Scholar 

  38. Tarnasky PR, Livingston EH, Jacobs KM, Zimmerman BJ, Guth PH, Garrick TR: Role of oxyradicals in cold water immersion restraint-induced gastric mucosal injury in the rat. Dig Dis Sci 35:173–177, 1990

    Google Scholar 

  39. Kawasaki S, Sugiyama S, Ishiguro N, Ozawa T, Miura T: Implication of superoxide radicals on ischemia-reperfusion-induced skeletal muscle injury in rats. Eur Surg Res 25:129–136, 1993

    Google Scholar 

  40. Kobayashi H, Nonami T, Kurokawa T, Sugiyama S, Ozawa T, Takagi H: Mechanism and prevention of ischemia-reperfusion-induced liver injury in rats. J Surg Res 51:240–244, 1991

    Google Scholar 

  41. Granholm T, Söder O: Constitutive production of lymphocyte activating factors by normal tissues in the adult rat. J Cell Biochem 46:143–151, 1991

    Google Scholar 

  42. Rubin JT, Lotze MT: Acute gastric mucosal injury associated with the systemic administration of interleukin-4. Surgery 111:274–280, 1992

    Google Scholar 

  43. Grijalva CV, Lindholm E, Novin D: Physiological and morphological changes in the gastrointestinal tract induced by hypothalamic intervention: An overview. Brain Res Bull 5(suppl 1):19–31, 1980

    Google Scholar 

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Authors and Affiliations

  1. From the Departments of Internal Medicine II and Biomedical Chemsitry, Faculty of Medicine, University of Nagoya, Tsuruma, Showa-ku, 466, Nagoya, Japan

    Eiji Hamajima MD, Satoru Sugiyama MD, PhD, Hiroshi Hoshino MD, Hidemi Goto MD, PhD, Yoshihisa Tsukamoto MD, PhD &  Takayuki Ozawa MD, PhD

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  1. Eiji Hamajima MD
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  2. Satoru Sugiyama MD, PhD
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  3. Hiroshi Hoshino MD
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  4. Hidemi Goto MD, PhD
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  5. Yoshihisa Tsukamoto MD, PhD
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  6. Takayuki Ozawa MD, PhD
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Hamajima, E., Sugiyama, S., Hoshino, H. et al. Effects of FK506, an immunosuppressive agent, on genesis of water-immersion stress-induced gastric lesions in rats. Digest Dis Sci 39, 713–720 (1994). https://doi.org/10.1007/BF02087412

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  • DOI: https://doi.org/10.1007/BF02087412

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