REGULATION OF NEUTROPHILS IN ULCERATIVE-COLITIS BY COLONIC FACTORS - A POSSIBLE MECHANISM OF NEUTROPHIL ACTIVATION AND TISSUE-DAMAGE

The mucosal injury of active ulcerative colitis (UC) could involve enh anced migration and activation of neutrophils (PMNs). Because, in vitr o, PMNs from patients with UC appear normal and are not therefore a li kely cause for the enhancements, we hypothesized an abnormal colonic m ilieu. We previously found that factors in the UC colonic milieu marke dly increase production of reactive oxygen species (ROS) by control PM Ns. We now hypothesize that these factors also regulate PMN surface in tegrins, that regulation of UC PMNs is different than that of control PMNs, and that the integrin regulation is consistent with the ROS regu lation. Using rectal dialysis, we sampled the colonic milieu in patien ts with active UC, in patients with inactive UC, and in control subjec ts. We monitored a key PMN adhesion molecule, CD11b. When control PMNs were tested, active UC rectal dialysate was almost as effective (+115 %) as N-formyl-methionyl-leucyl-phenylalanine (+132%) in up-regulating CD11b. When inactive UC PMNs were tested, baseline CD11b was 50% high er than that for control PMNs. In contrast, rectal dialysates failed t o up-regulate CD11b of inactive UC PMNs and in fact down-regulated CD1 1b. Preincubating control PMNs with UC rectal dialysates converted the ir CD11b response to PMN activators from up-regulation to down-regulat ion, mimicking inactive UC PMNs. Changes in intracellular calcium leve ls paralleled these changes in CD11b. Rectal dialysate-induced changes in both CD11b and calcium paralleled our previous findings on rectal dialysate-induced changes in ROS production. Thus the net overall effe ct of factors in the colonic milieu is a consistent and predictable re gulation of PMN function-proinflammatory in UC, anti-inflammatory in c ontrol subjects. These factors may be a critical part of the pathophys iology of UC.