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Robinson, Charles Edward
Mechanisms of inflammation in ulcerative colitis: a role for neutrophils and their free radicals

Order No. 9836285

Ulcerative Colitis (UC), a common form of Inflammatory Bowel Disease (IBD), is characterized by recurrent episodes of acute colonic inflammation, associated with abdominal pain, cramping, and bloody diarrhea. Since current treatments for IBD are not ideal, there is a need to develop better clinical management of UC. We chose to investigate pathophysiological mechanisms through which inflammation and tissue damage in UC occurs.

Hypothesis. (1) The final common pathway which leads to tissue damage in UC is mediated primarily by reactive oxygen species (ROS), (2) neutrophils are the main source of these ROS, and (3) these neutrophils are attracted to the colonic mucosa and activated by circulating (plasma) factors and local (colonic) factors.

Aims and methods. To support the above hypothesis, we proposed three aims: (Aim 1) To determine whether plasma from UC patients is pro-inflammatory. To this end, we evaluated the respiratory burst of PMN after incubation with plasma from UC patients. (Aim 2) To determine whether colonic factors in UC patients are pro-inflammatory. To this end, we evaluated the expression of the PMN adhesion molecule CD11b after stimulation with colonic factors from UC patients. (Aim 3) To determine whether colonic tissues from UC patients have abnormally high levels of oxidative products. To this end, we developed and used a novel immunoblotting technique to analyze oxidation products in colonic tissue from IBD patients. Colonic tissues were analyzed for protein carbonyls, nitrotyrosine, and 4- hydroxynonenal (4-HNE).

Results and discussion. (1) Plasma from UC patients significantly enhanced the PMN oxidative burst compared to plasma from controls. (2) Colonic factors from patients with UC significantly up-regulated CD11b compared to colonic factors from controls. These two results suggest that plasma and colonic factors in UC are pro-inflammatory, and may, therefore, perpetuate chronic inflammation. (3) Nitrotyrosine and 4-HNE were significantly higher in CD than in controls. In UC, nitrotyrosine and 4-HNE were also elevated, but these values did not reach significance. These results suggest that the ulcerations and tissue damage, which are hallmark features of IBD, may be the result of above normal oxidative stress. There were no differences between the groups for protein carbonyls. Source: DAI, 59, no. 06B, (1998): 2698

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