Anti-inflammatory effects of CGP 47969A, a novel inhibitor of proinflammatory cytokine synthesis, in rabbit immune colitis.
OBJECTIVE
Proinflammatory cytokines such as interleukin (IL) 1, IL-8, and tumor necrosis factor (TNF) have been implicated as primary mediators of intestinal inflammation. The aim of the present study was to determine the effects of a novel cytokine antagonist (CGP 47969A) in a rabbit model of acute colitis.


METHODS
Colitis was induced using the formalin-immune complex technique. Animals were pretreated intrarectally 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 colitis and twice daily thereafter until death 48 hours after the induction of colitis. The severity of inflammation of colonic tissue was assessed using histological analysis and myeloperoxidase activity assay, and IL-1 alpha, IL-8, TNF-alpha, and IL-1 receptor antagonist levels were determined.


RESULTS
Compared with vehicle, CGP 47969A (10 mg/kg) significantly reduced the acute inflammatory index by 58%, edema by 67%, necrosis by 99%, and myeloperoxidase activity by 49% (all P < 0.02) with efficacy similar to that of steroids. These effects were associated with a significant inhibition of colonic IL-1 alpha and IL-8 by 56% and 90%, respectively (p < 0.01).


CONCLUSIONS
Administration of CGP 47969A reduces inflammation and tissue damage in rabbit immune complex colitis through mechanisms involving the inhibition of mucosal proinflammatory cytokines.
Casini-Raggi
V
V
Department of Medicine, School of Medicine, University of Southern California, Los Angeles, USA.
Monsacchi
L
L
Vosbeck
K
K
Nast
C C
CC
Pizarro
T T
TT
Cominelli
F
F
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D003106:Colon / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006854:Hydrocortisone / Q000627:therapeutic use; D007105:Immune Complex Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D011817:Rabbits
D000894:Anti-Inflammatory Agents, Non-Steroidal; C092257:CGP 47969A; D016207:Cytokines; D007375:Interleukin-1; D016209:Interleukin-8; D010879:Piperazines; D009195:Peroxidase; D006854:Hydrocortisone