Effects of zinc on 2,4-dinitrobenzene sulfonic acid-induced ulcerative colitis in rats

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Abstract of the thesis entitled Effects of Zinc on 2,4-dutitrobenzene sulfonic acid-induced ulcerative colitis in rats Submitted by Luk Ho Hoi For the degree of Master of Medical Sciences at the University of Hong Kong In August 2000of the thesis entitled Effects of Zinc on 2,4-dutitrobenzene sulfonic acid-induced ulcerative colitis in rats Submitted by Luk Ho Hoi For the degree of Master of Medical Sciences at the University of Hong Kong In August 2000 Zinc is an essential element which participates in a wide range of cellular functions in eukaiyotic cells. Recently, it has been reported that this drug is effective against 2,4,6-trinitrobenzene sulfonic acid(TNBS)-mduced colitis. H e underlying mechanisms, however, have not been fully evaluated. TNBS-induced colitis is a hapten-induced animal model of experimental inflammatory bowel disease (IBD) that has been utili2ed to acquire insights into IBD pathogenesis. However, this agent is an explosive and pose some dangers to the operators. 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis is an alternative model that can be used safely with proper protective measures. As this model is relatively new, the pathogenic mechanism has not been fully elucidated. In the current study, DNBS was used to produce IBD in rats. The therapeutic effect of 7rnc in IBD was evaluated in this model. In addition, the possible pathogenic mechanisms of DNBS model were also investigated. Intrarectal administration of DNBS solution (30mg/rat, 0.25ml) produced acute and chronic inflammation and ulceration in the colon of rats with pathologic features closely resembling ulcerative colitis. The myeloperoxidase (MPO) activity was significantly increased by DNBS enema whereas the xanthine oxidase (XO) activity remained unchanged. These results indicated extensive neutrophil infiltration and activation of neutrophil associated NADPH oxidase in the inflamed colon. Repeated doses of teifenadine (12.5mg/kg, s.c.) and ranitidine (20mg/kgs ip.) markedly reduced lesion area and MPO activity. The XO activity, however, was not affected by two histamine receptor blockers. Oral administration of ketotifen (lOOjig/lOOmg), a mast cell stabilizer, also significantly inhibited the colonic lesions and MPO activity as well as XO activity. These data suggested that histamine released from mast cells may play an important role in the pathogenesis of DNBS-induced coKtis. Zinc enema at concentrations ranging from 3Qmg/kg to 120mg/kg reduced the colonic lesions induced by DNBS, MPO activity per unit tissue weight was also significantly reduced by zinc enema but the XO activity was not affected by rectal administration of zinc solution. Zinc solution when given by oral route did not have significant effects on DNBS model Our results therefore confirmed the therapeutic efficacy of zinc against experimental IBD. The decreased MPO activity implicated the reduced neutrophil mfiltratifm into the inflamed tissue. The underlying mechanisms of zinc against DNBS model thereby seem to be related to its inhibitory action on neutrophil infiltration and the subsequent reduction of free radical production. This effect is probably mediated via mast ceil stabilizing effect of zinc which blocks the release of histamine from mast cells. As XO activity was not influenced by DNBS or zinc enema, this enzyme is probably not involved in the pathogenesis of DNBS-induced colitis.