Abstract

The objective of this study was to quantitatively characterize the effects FK506 on the pathophysiology observed in a model of chronic granulomatous colitis in rats and compare these effects to those obtained with cyclosporin A (CyA). Chronic granulomatous colitis was induced in female Lewis rats via intramural (subserosal) injections of peptidoglycan/polysaccharide (PG/PS) into the distal colon. Rats then received daily injections (i.m.) of either vehicle for CyA (0.5 ml/kg cremophor), CyA in vehicle (25 mg/kg), saline (0.5 ml/kg) or FK506 (1 mg/kg in saline), beginning 7 days after PG/PS injection and continuing for an additional 2 weeks. On day 21, we found that the intramural injection of PG/PS produced a chronic colitis that was associated with hepatic and splenic granulomatous inflammation. Daily treatment with CyA or FK506 beginning 7 days after the induction of colitis resulted in significant inhibition in colonic mucosal permeability, colonic myeloperoxidase activity and plasma nitrate/nitrite levels when compared with their vehicle or untreated controls. In some instances, we noticed a significant vehicle-dependent anti-inflammatory activity. The incidence of peritoneal adhesions as well as the presence of hepatic and splenic granulomas induced by PG/PS were also significantly reduced in both the CyA- and FK506-treated groups. Taken together, these data suggest that immunosuppressive therapy is effective at attenuating both the colitis as well as the extraintestinal inflammation induced by PG/PS. We conclude that FK506 may be useful in the treatment of certain types of inflammatory bowel disease.