Skip to main content
  • Experimental Aspects of Gastrointestinal Inflammation New Approaches to Therapy of Gastrointestinal Inflammation General Inflammation Research Topics 3rd Meeting on Side Effects of Anti-Inflammatory Drugs and 13th European Workshop on Inflammation Verona, Italy
  • Published:

Therapeutic interventions in gastrointestinal disease based on an understanding of inflammatory mediators

Abstract

Whatever initiates inflammation, the final message mediating cellular invasion is chemical. This consideration allows rational development of anti-inflammatory treatments. Two main classes of chemotactic mediator are recognised. Water-soluble peptides, e.g. cytokines derived from macrophages and other cells, play an important integrating part in the early recruitment of neutrophils and mononuclear cells, and in the amplification of immune responses. Lipid-soluble mediators, of which leukotriene B4 is the most highly chemotactic for neutrophils, are important in secondary amplification.

In inflammatory bowel disease, we have shown evidence of increased synthesis of cytokines interleukin 1, 6 and 8. These are associated with activation of circulating monocytes in active Crohn's disease, of lamina propria macrophages in relapse of both ulcerative colitis and Crohn's disease, and development of adhesion molecules on vascular endothelium. Our studies show that interleukin 6 is selectively increased in Crohn's disease, whilst preliminary findings suggest that enhanced synthesis of interleukin 8 is particularly characteristic of ulcerative colitis.

Patterns of cytokine synthesis may, therefore, be of diagnostic value. They also offer the potential for therapeutic strategies since cytokine antagonists are becoming available.

We have also demonstrated increased synthesis of leukotrienes in active inflammatory bowel disease. Since leukotriene B4 is quantitatively the main chemotactic signal in the mucosa in inflammatory bowel disease during relapse, we investigated the therapeutic effect of suppressing leukotriene B4 synthesis by treating patients with fish oil (as Hi-EPA), giving 4.5 g daily of eicosapentaenoic acid. This competes for the 5-lipoxygenase enzymes, inhibiting leukotriene B4 and promoting synthesis of the less chemotactic product, LTB4. Ninety-six patients were treated for one year in a study structured to investigate both relapse and remission. Hi-EPA was well tolerated and compliance was good, since increased local tissue contractions of EPA were sustained whilst leukotriene synthesis of LTB5 rose and of LTB4 fell, by approximately 50%. Although fish oil had on overall effect on the number of days in remission, there was a significant steroidsparing effect during relapse. Recent studies with 5-lipoxygenase inhibitors also support the therapeutic value of modulating leukotriene synthesis in relapse.

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

References

  1. [1]

    A. J. Wakefield, A. M. Sawyer, A. O. Dhillon et al.,Pathogenesis of Crohn's disease: Multifocal gastrointestinal infarction. Lancet, 1057–1062 (1989).

  2. [2]

    Y. R. Mahida, P. D. E. Jones, T. K. Daneshmend and C. J. Hawkey,Peptide regulatory factors in the gut. InRecent Advances in Gastroenterology 8. (Ed. R. E. Pounder) pp. 61–80, Churchill Livingstone 1990.

  3. [3]

    M. Baggiolini, A. Walz and S. L. Kunkel,Neutrophil-activating peptide/interleukin 8, a novel cytokine that activates neutrophils. J. Clin. Invest.84, 1045–1049 (1989).

    PubMed  Google Scholar 

  4. [4]

    V. M. Elner, R. M. Streiter, S. G. Elner, M. Baggiolini, I. Lindley and S. L. Kunkel,Neutrophil chemotactic factor (IL8) gene expression by cytokine-treated retinal pigment epithelial cells. Am. J. Pathol.136, 745–750 (1990).

    PubMed  Google Scholar 

  5. [5]

    Y. R. Mahida, C. E. D. Lamming, A. Gallagher, A. B. Hawthorne and C. J. Hawkey,5-aminosalicylic acid is a potent inhibitor of IL1β production in organ culture of colonic biopsies from patients with inflammatory bowel disease. Gut32, 50–54 (1991).

    PubMed  Google Scholar 

  6. [6]

    Y. R. Mahida, L. Kurlak and C. J. Hawkey,Circulating and tissue interleukin 2 receptor levels in inflammatory bowel disease. Clin. Exp. Immunol.82, 75–80 (1990).

    PubMed  Google Scholar 

  7. [7]

    M. Z. Mazlam and H. J. F. Hodgson,Peripheral blood monocyte cytokine profiles differ between Crohn's disease and ulcerative colitis. Gut32, A493 (1991).

    Google Scholar 

  8. [8]

    S. A. Radema, S. J. H. Van Deventer and A. Cerami,Interleukin 1β is expressed predominantly by enterocytes in experimental colitis. Gastroenterology100, 1180–1186 (1991).

    PubMed  Google Scholar 

  9. [9]

    G. Malizia, A. Calabrese, M. Cottone et al.,Expression of leukocyte adhesion molecules by mucosal mononuclear phagocytes in inflammatory bowel disease. Gastroenterology100, 150–159 (1991).

    PubMed  Google Scholar 

  10. [10]

    C. Fiocchi, M. L. Hilfiker, K. R. Youngman, N. C. Doerder and H. Finke,Interleukin 2 activity of human intestinal mucosa mononuclear cells. Decreased levels in inflammatory bowel disease. Gastroenterology86, 734 (1984).

    PubMed  Google Scholar 

  11. [11]

    Y. R. Mahida, L. Kurlak and C. J. Hawkey,Circulating and tissue interleukin 2 receptor levels in inflammatory bowel disease. Clin. Exp. Immunol.82, 75–80 (1990).

    PubMed  Google Scholar 

  12. [12]

    Y. R. Mahida, A. Gallagher, L. Kurlak and C. J. Hawkey,High circulating levels of interleukin 6 in Crohn's disease but not ulcerative colitis. Gut32, 50–54 (1991).

    PubMed  Google Scholar 

  13. [13]

    Y. R. Mahida, M. Ceska, F. Effenberger, L. Kurlak, I. Lindley and C. J. Hawkey,A specific role for neutrophil activating peptide/interleukin 8 (NAP1/IL8) in ulcerative colitis? Clin. Sci. (abstract, in press).

  14. [14]

    P. Sharon, M. Ligumsky, D. Rachmilewitz and U. Zor,Role of prostaglandins in ulcerative colitis. Enhanced production during active disease and inhibition by sulphasalazine. Gastroenterology75, 638–40 (1978).

    PubMed  Google Scholar 

  15. [15]

    C. J. Hawkey and S. C. Truelove,Effect of prednisolone on prostaglandin synthesis by rectal mucosa in ulcerative colitis. Gut22, 190–193 (1981).

    PubMed  Google Scholar 

  16. [16]

    C. J. Hawkey and S. C. Truelove,Inhibition of prostaglandin synthetase in human rectal mucosa. Gut24, 213–217 (1983).

    PubMed  Google Scholar 

  17. [17]

    C. J. Hawkey, F. Karmeli and D. Rachmilewitz,Imbalance of prostacyclin and thromboxane synthesis in Crohn's disease. Gut24, 881–885 (1983).

    PubMed  Google Scholar 

  18. [18]

    N. K. Boughton-Smith, C. J. Hawkey and B. J. R. Whittle,The biosynthesis of lipoxygenase and cyclooxygenase products from (14C) arachidonic acid in human colonic mucosa. Gut24, 1176–1182 (1983).

    PubMed  Google Scholar 

  19. [19]

    E. A. Lobos, P. Sharon and W. F. Stenson,Chemotactic activity in inflammatory bowel disease: Role of leukotriene B4. Dig. Dis. Sci.32, 1380–1388 (1987).

    PubMed  Google Scholar 

  20. [20]

    C. J. Hawkey, N. K. Boughton-Smith and B. J. R. Whittle,Modulation of arachidonic acid metabolism by sulphasalazine. Dig. Dis. Sci.12, 1161–1166 (1985).

    Google Scholar 

  21. [21]

    K. Lauritsen, L. S. Laursen, K. Bukhave and J. Rask-Masden,Effects of topical 5-aminosalicylic acid and prednisolone on prostaglandin E 2 and leukotriene B 4 levels determined by equilibrium in vivo dialysis of rectum in relapsing ulcerative colitis. Gastroenterology91, 837–44 (1986).

    Google Scholar 

  22. [22]

    T. R. J. Stevens, S. F. Smith, T. Smith, R. J. Flower and D. S. Rampson,Lipocortin-1 antibodies in inflammatory bowel disease. Gastroenterology32, A561 (1991).

    Google Scholar 

  23. [23]

    A. B. Hawthorne, T. K. Daneshmend, C. J. Hawkey, M. Z. Shaheen, T. J. Edwards, B. L. Filipowicz and S. J. Everitt,Fish oil in ulcerative colitis: Final results of a controlled clinical trial. Gastroenterology98, A174 (1990).

    Google Scholar 

  24. [24]

    A. B. Hawthorne, B. L. Filipowicz, T. J. Edwards and C. J. Hawkey,High dose eicosapentaenoic acid ethyl ester: Effects on lipids and neutrophil leukotriene production in normal volunteers. Br. J. Clin. Pharmacol.30, 187–194 (1990).

    PubMed  Google Scholar 

  25. [25]

    W. F. Stenson, K. Lauritsen and J. Laursen et al.,A clinical trial of zileuton, a specific inhibitor of 5-lipoxygenase, in ulcerative colitis. Gastroenterology100, A253 (1991).

    Google Scholar 

  26. [26]

    A. B. Hawthorne, L. Kurlak, N. K. Boughton-Smith, B. J. R. Whittle and C. J. Hawkey,Inhibition of rectal biopsy leukotriene (LT) synthesis by the 5-lipoxygenase (5LO) inhibitor BWA4C ulcerative colitis (UC). Gastroenterology98, A174 (1990).

    Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hawkey, C.J., Mahida, Y.R. & Hawthorne, A.B. Therapeutic interventions in gastrointestinal disease based on an understanding of inflammatory mediators. Agents and Actions 36, C22–C26 (1992). https://doi.org/10.1007/BF01996091

Download citation

Keywords

  • Inflammatory Bowel Disease
  • Ulcerative Colitis
  • Eicosapentaenoic Acid
  • LTB4
  • Active Inflammatory Bowel Disease