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

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.