MODULATION OF NEUTROPHIL FUNCTION BY NOVEL COLONIC FACTORS - POSSIBLEROLE IN THE PATHOPHYSIOLOGY OF ULCERATIVE-COLITIS

Tissue damage in acute ulcerative colitis (UC) may be triggered by neu trophils (PMNs) and their inflammatory mediators such as reactive oxyg en species (ROS). Because circulating PMNs appeared normal in subjects with UC, we hypothesized that the critical abnormality that attracts and activates PMNs in UC is a local colonic factor. Accordingly, the c olonic milieu was sampled by using in vivo rectal dialysis (mel wt les s than or equal to 12 kd). Normal PMNs were exposed in vitro to rectal dialysates (RD) from control subjects (cRD) or subjects with active U C (aRD) or inactive UC (iRD). PMN-derived ROS were measured by chemilu minescence. cRD did not increase ROS production by unstimulated PMNs; aRD significantly and concentration-dependently increased ROB; IRD gav e intermediate results. cRD inhibited the PMN-stimulating effects of b oth the bacterial peptide formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol myristate acetate (PMA), aRD and IRD blunted the effect o f fMLP and PMA significantly less than did cRD. Rectal dialysates from 44% of subjects with active UC exaggerated the fMLP effect, whereas p otentiation occurred for only 13% of cRDs and 18% of iRDs, cRD precond itioned with either activated or nonactivated PMNs was not significant ly different than unconditioned cRD. We thus infer the existence of co lonic factors in UC that (1) can trigger PMNs to produce ROS and (2) h ave a proinflammatory modulatory effect on bacterial peptide-induced, PMN-mediated ROS production, thereby initiating or perpetuating inflam mation and eventually causing tissue damage. The differences in coloni c milieu between controls and active UC does not appear to be due to i nfiltrated mucosal PMNs, because incubation of cRD with PMNs in UC did not change cRD effects on PMN function.