ATTENUATION OF EPITHELIAL INJURY IN ACUTE EXPERIMENTAL COLITIS BY IMMUNOMODULATORS

Intestinal epithelial permeability can be modulated by the immune syst em and can be greatly increased by transepithelial migration of neutro phils. Since immunosuppressants have been reported to inhibit the abil ity of neutrophils to migrate, we assessed the effects of two immunosu ppressants on epithelial permeability and granulocyte infiltration in a model of acute colitis. Epithelial permeability was measured at 3 an d 6 h after induction of colitis in the rabbit by intracolonic adminis tration of trinitrobenzene sulfonic acid. At these times, blood-to-lum en leakage of Cr-51-EDTA was elevated by approximately 8- and 18-fold, respectively, above levels observed in healthy controls. Pretreatment with either of the immunosuppressants (cyclosporin A and L-683,590) s ignificantly reduced the changes in Cr-51-EDTA leakage observed at the latter time point. These drugs also significantly attenuated granuloc yte infiltration of the colon after induction of colitis, as measured by tissue myeloperoxidase activity. Unlike the immunosuppressants, mis oprostol, a prostaglandin analogue, attenuated the increases in coloni c permeability but had no effect on granulocyte infiltration in this m odel. These results demonstrate that two structurally unrelated immuno suppressants are capable of markedly reducing neutrophil infiltration and the colonic permeability changes observed in an experimental model of acute colitis, although the mechanisms through which these effects are produced remain unclear.