Abstract
Though the mechanism of tissue damage induced by colonic inflammation in ulcerative colitis is unknown, it has been established that the inflammatory mediator and potent neutrophil (PMN) chemotaxin, leukotriene B4(LTB4), is present in elevated amounts in the inflamed mucosa. The unique role of 5-lipoxygenase in the production of leukotrienes has made it a target for inhibition. This study used a rat model of acute colonic inflammation induced by a single IP injection of Mitomycin-C to test the efficacy of a specific and potent 5-lipoxygenase inhibitor zileuton in the treatment of colonic inflammation. We hypothesized that after inducing colitis in rats with mitomycin-C, the administration of oral zileuton would inhibit leukotriene production, thus preventing PMN infiltration and subsequent tissue damage. Zileuton decreased colonic tissue damage as measured by Histological score. However, zileuton did not significantly decrease neutrophil infiltration measured by mucosal PMN or myeloperoxidase (MPO) levels. Although zileuton was successful in significantly decreasing the frequency of severe colitis in our model, the fact that the decrease in PMN count and MPO level was not statistically significant suggests that another mechanism may be involved in its anti-inflammatory effect.
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References
Kirsner, J. B., andShorter, R. G. 1982. Recent development in nonspecific inflammatory bowel disease.New Engl. J. Med. 306, 775–837.
Young, P. R., Bell, R. L., Lanni, C., Summers, J. B., Brooks, D. W., andCarter, G. W. 1991. Inhibition of leukotriene biosynthesis in the rat peritoneal cavity.European Journal of Pharm. 205, 259–266.
Lauritsen, K., L. S. Laursen, K. Bukhave, andJ. Rask-Madsen. 1986. Effects of topical 5-aminosalicyclic acid and prednisolone on prostaglandin E2 and leukotriene B4 levels determined by equilibrium in vivo dialysis of rectum in relapsing ulcerative colitis.Gastroenterology. 91, 837–844.
Nishida, T., H. Miwa, A. Shigematsu, M. Yamamoto, M. Iida, M. Fujishima. 1987. Increased arachidonic acid composition of phospholipids in colonic mucosa from patients with active ulcerative colitis.Gut. 28, 1002–1007.
Hawkes, J. S., L. G. Cleland, andM. J. James. 1993. The effect of methotrexate on lipoxygenase metabolism in neutrophils from rats: in vivo and ex vivo studies.Agents Actions. 40, 181–185.
Keshavarzian, A., Sedghi, S., Kanofsky, J., List, I., Robinson, C., Ibrahim, C., andWinship, D. 1992. Excessive Production of Reactive Oxygen Metabolites by Inflamed Colon: Analysis by Chemiluminescence Probe.Gastroenterology. 103, 177–185.
Laursen, L. S., J. Naesdal, K. Bukhave, K. Lauritsen, andJ. Rask-Madsen. 1990. Selective 5-lipoxygenase inhibition in ulcerative colitis.Lancet. 335, 683–685.
Keshavarzian, A., Doria, M., Sedghi, S., Kanofsky, J., Hecht, D., Holmes, E., Ibrahim, C., List, T., Gaginella, T., Parveen, S., andFields, J. Z. 1992. Mitomycin-C-induced colitis in rats: A new animal model of acute colonic inflammation implicating reactive oxygen species.Journal of Lab. and Clinical Med. 120, 778–791.
Keshavarzian, A., G. Morgan, S. Sedghi, J. H. Gordon, andM. Doria. 1990. Role of reactive oxygen metabolites in experimental colitis.Gut. 31, 786–790.
Krawisz, J. E., P. Sharon, andW. F. Stenson. 1984. Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity.Gastroenterology. 87, 1344–1350.
Kirsner, J. B., andR. G. Shorter. 1982. Recent developments in “nonspecific” inflammatory bowel disease.N. Engl. J. Med. 306, 837–848.
Hodgson, H. J. F., andD. P. Jewell. 1978. The humoral immune system in inflammatory bowel disease.Dig. Dis. 23, 123–128.
O'Dorisio, M. S. 1986. Neuropeptides and gastrointestinal immunity.Am. J. Med. 81, 74–81.
Sleisenger, M. H., andJ. S. Fordtran. 1989.Gastrointestinal Disease. Vol. 4. Philadelphia, W. B. Saunders.
Shanahan, F., andP. Anton. 1988. Neuroendocrine modulation of the immune system; possible implications for inflammatory bowel disease.Dig. Dis. Sci. 33, 41–49S.
Collawn, C., Rubin, P., Perez, N., Babadilla, J., Cabrera, G., Reyes, E., Borovoy, J., andKershenobich, D. 1992. Phase II study of the safety and efficacy of a 5-lipoxygenase inhibitor in patients with ulcerative colitis.The Am. J. of Gastroenterology. 87, 342–346.
Fretland, D. J., S. W. Djuric, andT. S. Gaginella. 1990. Prostaglandins leukotrienes essent.Fatty Acids. 41, 215–233.
Kennedy, N. P., andP. W. N. Keeling. 1987. Aliment.Pharmacol. Ther. 1, 263–272.
Thomsen, M. K., andI. Ahnfelt-Ronne. 1991. Leukotrienes. A review of the significance for disease in man and the possibilities for therapeutic intervention.Agents Actions. 153, 173–176.
Rask-Madsen, J., K.Bukhave, L. S.Laursen, and K.Lauritsen. 1992. 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease.Agents and Actions Special Conference Issue. pp. C37–C46.
Laursen, L. S., Lauritsen, K., Bukhave, K., Rask-Madsen, J., Jacobsen, D., Naesdal, J., Goebell, H., Peskar, B., Rubin, P. D., Swanson, L. F., Kesterson, J. W., Keshavarzian, A., Kozarek, R., Hanauer, S., Cort, D., andStevenson, W. F. 1994. Selective 5-lipoxygenase inhibition by zileuton in the treatment of relapsing ulcerative colitis: a randomized double-blind placebo-controlled multicentre trial.European J. of Gastroenterology and Hepatology. 6, 209–215.
Bell, R. L., Lanni, C., Malo, P. E., Brooks, D. W., Stewart, A. O., Hansen, R., Rubin, P., andCarter, G. W. 1993. Preclinial and clinical activity of zileuton and A-78773.Annals of New York Academy of Sciences. 696, 205–215.
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Zarif, A., Eiznhamer, D., Callaghan, C. et al. The effect of a selective 5-lipoxygenase inhibitor, zileuton, on tissue damage in acute colonic inflammation in rats. Inflammation 20, 217–227 (1996). https://doi.org/10.1007/BF01488200
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DOI: https://doi.org/10.1007/BF01488200