Skip to main content
SpringerLink
Log in

Modulatory Effects of Plasma and Colonic Milieu of Patients with Ulcerative Colitis on Neutrophil Reactive Oxygen Species Production in Presence of a Novel Antioxidant, Rebamipide

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Rebamipide protects gastrouintestinal mucosal integrity against reactive oxygen species (ROS). The effect of rebamipide on the capability of PMNs to produce ROS in the presence of plasma and rectal dialysates (RD) of control and ulcerative colitis (UC) subjects was evaluated. We recruited six healthy volunteers for obtaining PMNs, control plasma, and control RD and six patients with inactive UC for obtaining plasma and RD. PMNs were activated using fMLP, and ROS was measured by fluorescent microplate assay (DCFD). Rebamipide significantly inhibited the neutrophil respiratory burst by 45%. Plasma from both control subjects and UC patients significantly blunted the fMLP-induced respiratory burst. However, the plasma of the UC patients was significantly less inhibitory than the plasma of control subjects. RD from control subjects significantly blunted the fMLP-induced respiratory burst while, RD from patients with UC did not. Rebamipide maintained its antioxidant effects in the presence of plasma or RD obtained from both controls and UC patients. In conclusion, partial loss of the inhibitory effects of plasma and RD in patients with UC may contribute to oxidative-induced tissue damage in UC and rebamipide antioxidant properties were not hampered by the biological milieu of patients with UC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Klebanoff SJ: Phagocytic cells: Products of oxygen metabolism. In Inflammation, Basic Principles and Clinical Correlates. JI Gallin, IM Goldstein, R Snyderman (eds). New York, Raven Press, 1992, pp 391–444

    Google Scholar 

  2. Halliwell B, Cross CE: Oxygen derived species: their relation to human disease and environmental stress. Envirom Health Perspect 102(suppl) 10:5–12, 1994

    Google Scholar 

  3. Kirsner JB, Shorter RG: Recent developments in non-specific inflammatory bowel disease. N Engl J Med 306:775–784, 1982

    PubMed  Google Scholar 

  4. Weiss SJ: Tissue destruction by neutrophils. N Engl J Med 107:365–376, 1989

    Google Scholar 

  5. Parks D, Buckley G, Granger N: Role of oxygen free radicals in digestive tract disease. Surgery 94:415–418, 1983

    PubMed  Google Scholar 

  6. Keshavarzian A, Fields JZ: A radical perspective on ulcerative colitis. J Gastroenterol Hepatol 10:208–209, 1995

    PubMed  Google Scholar 

  7. Keshavarzian A, Morgan G, Sedghi S, Gordon JH, Doria M: Role of reactive oxygen metabolites in experimental colitis. Gut 31:786–790, 1990

    PubMed  Google Scholar 

  8. McKenzie SJ, Baker MS, Buffinton GD: Evidence of oxidantinduced injury to epithelial cells during inflammatory bowel disease. Clin Invest 98:136–141, 1996

    PubMed  Google Scholar 

  9. Halliwell B, Gutteridge JMC (eds). Free Radicals in Biology and Medicine, 2nd ed. Clarendon, Oxford, UK, 1989

    Google Scholar 

  10. Keshavarzian A, Sedghi S, Kanofsky J, et al: Excessive production of reactive oxygen metabolites by inflamed colon: Analysis by chemiluminescence probe. Gastroenterology 103:177–185, 1992

    PubMed  Google Scholar 

  11. Sedghi S, Fields JZ, Klamut M, et al: Increased production of luminol enhanced chemiluminescence by the inflamed colonic mucosa in patients with ulcerative colitis. Gut 34:1191–1197, 1993

    PubMed  Google Scholar 

  12. Williams JG, Hughes LE, Hallett MB: Toxic oxygen metabolite production by circulating phagocytic cells in inflammatory bowel. Gut 31:187–193, 1990

    PubMed  Google Scholar 

  13. Verspaget HW, Elmgreen J, Weterman IT, Pena AS, Riis P, Lamers CB: Impaired activation of the neutrophil oxidative metabolism in chronic inflammatory bowel disease. Scand J Gastroenterol 21:1124–1130, 1986

    PubMed  Google Scholar 

  14. Kurokawa T, Joh T, Ikai M, Seno K, Yokoyama Y, Itoh M: Rebamipide protects against oxygen radical-mediated gastric mucosal injury in rats. Dig Dis Sci. 43:113S–117S, 1998

    PubMed  Google Scholar 

  15. Sakurai K, Yamasaki K: Protective effect of Rebamipide against hydrogen peroxide induced hemorrhagic mucosal lesions in rat stomach. Jpn J Pharmacol 64:229–234, 1994

    PubMed  Google Scholar 

  16. Ogino K, Hobara T, Ishiyama H, et al: Antiulcer mechanism of action of rebamipide, a novel anti-ulcer compound, on diethyldithiocarbamate-induced antral gastric ulcers in rats. Eur J Pharmacol 212:9–13, 1992

    PubMed  Google Scholar 

  17. Yamasaki K, Ishiyama H, Imaizumi T, Kanbe T, Yabuuchi Y: Effect of OPC-12759, a novel antiulcer agent, on chronic and acute experimental gastric ulcer and gastric secretion in rats. Jpn J Pharmacol 49:441–448, 1989

    PubMed  Google Scholar 

  18. Yamasaki K, Kanbe T, Chijiwa T, Ishiyama H, Morita S: Gastric mucosal protection by OPC-12759, a novel anti-ulcer compound in the rat. Eur J Pharm 142:23–29, 1987

    PubMed  Google Scholar 

  19. Murakami K, Okajima K, Harada N, Isobe H, Okabe H: Rebamipide prevents indomethacin-induced gastric mucosal lesion formation by inhibiting activation of neutrophils in rats. Dig Dis Sci 43:139S–142S, 1998

    PubMed  Google Scholar 

  20. Yoshida M, Wakabayashi G, Ishikawa H, et al: Rebamipide attenuates gastric microcirculatory disturbances in the early period after thermal injury in rats. Dig Dis Sci 43:148S–153S, 1998

    PubMed  Google Scholar 

  21. Keshavarzian A, Haydek JM, Jacyno M, Holmes EW, Harford F: Modulatory effects of the colonic milieu on neutrophil oxidative burst: A possible pathogenic mechanism of ulcerative colitis. J Lab Clin Med 130:216–225, 1997

    PubMed  Google Scholar 

  22. Kazi N, Fields JZ, Sedghi S, et al: Modulation of neutrophil function by novel colonic factors: Possible role in the pathophysiology of ulcerative colitis. J Lab Clin Med 126:70–80, 1995

    PubMed  Google Scholar 

  23. Robinson CE, Kottapalli V, D'Astice M, Fields JZ, Winship D, Keshavarzian A: Regulation of neutrophils in ulcerative colitis by colonic factors: A possible mechanism of neutrophil activation and tissue damage. J Lab Clin Med 130:590–602, 1997

    PubMed  Google Scholar 

  24. Keller HU, Hess MW, Cottier H: Inhibiting effects of human plasma and serum on neutrophil random migration and chemotaxis. Blood 44:843–848, 1974

    PubMed  Google Scholar 

  25. Walker JR, Smith MJ, Ford-Hutchinson AW, Billimoria FJ: Mode of action of an antiinflammatory fraction from normal human plasma. Nature 254:444–446, 1975

    PubMed  Google Scholar 

  26. Keshavarzian A, Fusunyan RD, Jacyno M, Winship D, Mac-Dermott RP, Sanderson IR: Increased interleukin-8 (IL-8) in rectal dialysate from patients with ulcerative colitis: Evidence for a biological role for IL-8 in inflammation of the colon. Am J Gastroenterol 94:704–712, 1999

    PubMed  Google Scholar 

  27. Hong KW, Kim KE, Rhim BY, Lee WS, Kim CD: Effect of rebamipide on liver damage and increased tumor necrosis factor in a rat model of endotoxin shock. Dig Dis Sci 43:154S–159S, 1998

    PubMed  Google Scholar 

  28. Kim CD, Kim HH, Hong KW: Inhibitory effect of Rebamipide on the neutrophil adherence stimulated by conditioned media from Helicobacter pylori-infected gastric epithelial cells. J Pharmacol Exp Ther 288:133–138, 1999

    PubMed  Google Scholar 

  29. Kim CD, Kim YK, Lee SH, Hong KW: Rebamipide inhibits neutrophil adhesion to hypoxia/reoxygenation-stimulated endothelial cells via nuclear factor-kappaB-dependent pathway. J Pharmacol Exp Ther 294:864–869, 2000

    PubMed  Google Scholar 

  30. Kobayashi T, Zinchuk VS, Garcia del Saz E, et al: Suppressive effect of rebamipide, an antiulcer agent, against activation of human neutrophils exposed to formyl-methionyl-leucylphenylalanine. Histol Histopathol 15:1067–1076, 2000

    PubMed  Google Scholar 

  31. Danielsson D, Jurstrand M: Nonopsonic activation of neutrophils by Helicobacter pylori is inhibited by rebamipide. Dig Dis Sci 43:167S–173S, 1998

    PubMed  Google Scholar 

  32. Iinuma S, Naito Y, Yoshikawa T, et al. In vitro studies indicating antioxidative properties of rebamipide. Dig Dis Sci 43:35S–39S, 1998

    PubMed  Google Scholar 

  33. Yoshida N, Yoshikawa T, Iinuma S, et al: Rebamipide protects against activation of neutrophils by Helicobacter pylori. Dig Dis Sci 41:1139–1144, 1996

    PubMed  Google Scholar 

  34. Suzuki M, Miura S, Mori M, et al: Rebamipide, a novel antiulcer agent, attenuates Helicobacter pylori induced gastric mucosal cell injury associated with neutrophil derived oxidants. Gut. 35:1375–1378, 1994

    PubMed  Google Scholar 

  35. Kim C, Hong K: Preventive effect of Rebamipide on gastric mucosal cell damage evoked by activation of formyl-methionylleucyl-phenylalanine receptors of rabbit neutrophils. J Pharm Exp Ther 281:478–483, 1997

    Google Scholar 

  36. Yoshikawa T, Naito Y, Tanigawa T, Kondo M: Free radical scavenging activity of the novel anti-ulcer agent rebamipide studied by electron spin resonance. Arzneimittelforschung 43:363–366, 1993

    PubMed  Google Scholar 

  37. Naito Y: Hydroxyl radical scavenging by rebamipide and related compounds; electron paramagnetic resonance study. Free Radic Biol Med 18:117–123, 1995

    PubMed  Google Scholar 

  38. Iinuma S, Yoshikawa T, Takahashi S, Takemura T, Yoshida N, Kondo M: In vitro studies indicating anti-oxidative properties of Rebamipide. Dig Dis Sci 43:35S–39S, 1998

    PubMed  Google Scholar 

  39. Aihara M, Imagawa K, Funakoshi Y, Ohmoto Y, Kikuchi M: Effects of rebamipide on production of several cytokines by human peripheral blood mononuclear cells. Dig Dis Sci 43:160S–166S, 1998

    PubMed  Google Scholar 

  40. Aihara M, Azuma A, Takizawa H, et al: Molecular analysis of suppression of interleukin-8 production by rebamipide in Helicobacter pylori-stimulated gastric cancer cell lines. Dig Dis Sci 43:174S–180S, 1998

    PubMed  Google Scholar 

  41. Watanabe S, Wang XE, Hirose M, Osada T, Tanaka H, Sato N: Rebamipide prevented delay of wound repair induced by hydrogen peroxide and suppressed apoptosis of gastric epithelial cells in vitro. Dig Dis Sci 43:107S–112S, 1998

    PubMed  Google Scholar 

  42. Kleine A, Kluge S, Peskar BM: Stimulation of prostaglandin biosynthesis mediates gastroprotective effect of Rebamipide in rats. Dig Dis Sci 38:1441–1449, 1993

    PubMed  Google Scholar 

  43. Sun WH, Tsuji S, Tsujii M, et al: Induction of cyclooxygenase-2 in rat gastric mucosa by Rebamipide, a mucoprotective agent. J Pharmacol Exp Ther 295:447–452, 2000

    PubMed  Google Scholar 

  44. Gardiner KR, Anderson NH, Rowlands BJ, Barbul A: Colitis and colonic mucosal barrier dysfunction. Gut 7:530–535, 1995

    Google Scholar 

  45. Hollander D: The intestinal permeability barrier: A hypothesis as to its regulation and involvement in Crohn's disease. Scand J Gastroenterol 7:721–726, 1992

    Google Scholar 

  46. Zuckerman MJ, Watts MT: Intestinal permeability to 51Cr-EDTA in-patients with ulcerative colitis. Am J Gastroenterol 88:1978–1979, 1993

    PubMed  Google Scholar 

  47. Hollander D: Crohn's disease—a permeability disorder of the tight junction? Gut 26:1621–1624, 1988

    Google Scholar 

  48. Von Ritter C, Grisham MB, Hollwarth M, Inauen W, Granger DN: Neutrophil-derived oxidants mediated formyl-methionylleucyl-phenylalanine-induced increase in mucosal permeability in rats. Gastroenterology 97:778–780, 1995

    Google Scholar 

  49. Banan A, Choudhary S, Zhang Y, Keshavarzian A: Role of the microtubule cytoskeleton in protection by epidermal growth factor and transforming growth factor-? against oxidantinduced barrier disruption in a human colonic cell line. Free Radic Biol Med 28:727–738, 2000

    PubMed  Google Scholar 

  50. Thierry R., Burkhard C, Finci-Cerkez V, Meda P: Oxidative stress causes a PKC-independent increase of paracellular permeability in an in vitro epithelial model. Am. J Respir Cell Mol Biol 9:496–504, 1993

    PubMed  Google Scholar 

  51. Rao RK, Baker RD, Baker SS, Gupta A, Holycross M: Oxidant-induced disruption of intestinal epithelial barrier function: Role of protein tyrosine phosphorylation. Am J Physiol 273:G812–G823, 1997

    PubMed  Google Scholar 

  52. Banan A, Fitzpatrick L, Zhang Y, Keshavarzian A: OPC-compounds prevent oxidant-induced carbonylation and depolymerization of the F-actin cytoskeleton and intestinal barrier hyperpermeability. Free Radic Biol Med 30:287–298, 2001

    PubMed  Google Scholar 

  53. Sakurai K: Protection by rebamipide against acetic acid induced colitis in rats: Relationship with its anti-oxidative activity. Dig Dis Sci 43:125S–133S, 1998

    PubMed  Google Scholar 

  54. Iwai A, Iwashita E: Changes in colonic inflammation induced by dextran sulfate sodium (DSS) during short-and long-term administration of rebamipide. Dig Dis Sci 43:143S–147S, 1998

    PubMed  Google Scholar 

  55. Zea-Iriarte W, Makiyam K, Goto S, et al: Impairment of antioxidants in colonic epithelial cells isolated from trinitrobenzene sulphonic acid-induced colitis rats. Protective effect of Rebamipide. Scand J Gastroenterol 31:985–992, 1996

    PubMed  Google Scholar 

  56. Makiyama K, Takeshima F, Kawasaki H, Zea-Iriarte WL: Anti-inflammatory effect of rebamipide enema on proctitis type ulcerative colitis: A novel therapeutic alternative. Am J Gastroenterol 95:1838–1839, 2000 (letter)

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine (Division of Digestive Disease), Pharmacology, Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois, USA

    A. Farhadi, A. Keshavarzian, E. Mutlu, Y. Zhang & A. Banan

  2. Otsuka Maryland Research Institute, Rockville, Maryland, USA

    L.R. Fitzpatrick

Authors
  1. A. Farhadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Keshavarzian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L.R. Fitzpatrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Mutlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Banan
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Farhadi, A., Keshavarzian, A., Fitzpatrick, L. et al. Modulatory Effects of Plasma and Colonic Milieu of Patients with Ulcerative Colitis on Neutrophil Reactive Oxygen Species Production in Presence of a Novel Antioxidant, Rebamipide. Dig Dis Sci 47, 1342–1348 (2002). https://doi.org/10.1023/A:1015382800434

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1015382800434

Search

Navigation