ANTIINFLAMMATORY EFFECTS OF CGP 47969A, A NOVEL INHIBITOR OF PROINFLAMMATORY CYTOKINE SYNTHESIS, IN RABBIT IMMUNE COLITIS

Background and Aims: Proinflammatory cytokines such as interleukin (IL ) 1, IL-8, and tumor necrosis factor (TNF) have been implicated as pri mary mediators of intestinal inflammation. The aim of the present stud y was to determine the effects of a novel cytokine antagonist (CGP 479 69A) in a rabbit model of acute colitis. Methods: Colitis was induced using the formalin-immune complex technique. Animals were pretreated i ntrarectally with CGP 47969A (30, 10, or 3 mg/kg), hydrocortisone (0.8 mg/kg), or Vehicle (4 mL saline) 2 hours before the induction of coli tis and twice daily thereafter until death 48 hours after the inductio n of colitis. The severity of inflammation of colonic tissue was asses sed using histological analysis and myeloperoxidase activity assay, an d IL-1 alpha, IL-8, TNF-alpha, and IL-1 receptor antagonist levels wer e determined. Results: Compared with vehicle, CGP 47969A (10 mg/kg) si gnificantly reduced the acute inflammatory index by 58%, edema by 67%, necrosis by 99%, and myeloperoxidase activity by 49% (all P < 0.02) w ith efficacy similar to that of steroids. These effects were associate d with a significant inhibition of colonic IL-1 alpha and IL-8 by 56% and 90%, respectively (P < 0.01). Conclusions: Administration of CGP 4 7969A reduces inflammation and tissue damage in rabbit immune complex colitis through mechanisms involving the inhibition of mucosal proinfl ammatory cytokines.