Millar, Andrew David; (1997) Reactive oxygen species and the role of antioxidant therapy in inflammatory bowel disease. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

A proven role for antioxidant therapy in inflammatory bowel disease (IBD) would help establish the pathogenic importance of reactive oxygen species (ROS) and may provide new therapies with low toxicity. The major findings of the work for this thesis were as follows: ROS production, as measured by the chemiluminescence response, of colonic biopsies from acetic acid-induced colitis in rats correlated with the macroscopic and microscopic scores of inflammation. o A method for assessing the antioxidant actions of novel IBD therapy was established by demonstrating that conventional antioxidants, and standard therapies for IBD, alter the chemiluminescence responses of acetic acid-induced colitis biopsies similarly to ulcerative colitis (UC) biopsies (previously published data). The novel compounds, amflutizole and LY231617 were potent antioxidants. o The chemiluminescence response of UC biopsies correlated with clinical disease activity and sigmoidoscopic scores, and with mucosal neutrophil infiltration. Recombinant human recombinant manganese superoxide dismutase (rh-MnSOD) was not an effective antioxidant using acetic acid-induced colitis biopsies. Pretreatment of rats with acetic acid-induced colitis with intraluminal rh-MnSOD did not alter the macroscopic or microscopic scores of inflammation nor chemiluminescence: Rh-MnSOD is probably not, therefore, a suitable agent for topical therapy in IBD. • The iron chelators, desferrioxamine and 1,10-phenanthroline, reduced ROS production by inflamed biopsies from UC. • A pilot trial of antioxidant nutrients, selenium, β-carotene, ascorbate, a-tocopherol and methionine, in active UC demonstrated no adverse events, remission in 4/10 patients, and significant improvements in stool frequency, rectal bleeding and sigmoidoscopic score, but not rectal mucosal histology, ROS production, or plasma thiobarbituric acid reactive substances. This work has shown that the acetic acid-induced colitis model in rats can be used for screening for novel antioxidant therapy, confirms that ROS are likely to be pathogenic in UC, and suggests that antioxidant therapy, using amflutizole, LY231617, iron chelators or antioxidant nutrients, merits controlled therapeutic assessment in IBD.

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