A potent human C5a receptor antagonist protects against disease pathology in a rat model of inflammatory bowel disease

Woodruff, Trent M., Arumugam, Thiruma V., Shiels, Ian A., Reid, Robert C., Fairlie, David P. and Taylor, Stephen M. (2003) A potent human C5a receptor antagonist protects against disease pathology in a rat model of inflammatory bowel disease. Journal of Immunology, 171 10: 5514-5520.


Author Woodruff, Trent M.
Arumugam, Thiruma V.
Shiels, Ian A.
Reid, Robert C.
Fairlie, David P.
Taylor, Stephen M.
Title A potent human C5a receptor antagonist protects against disease pathology in a rat model of inflammatory bowel disease
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
1550-6606
Publication date 2003-11-15
Sub-type Article (original research)
Volume 171
Issue 10
Start page 5514
End page 5520
Total pages 7
Place of publication Bethesda, MD, U.S.A.
Publisher American Association of Immunologists
Language eng
Subject C1
730102 Immune system and allergy
320502 Basic Pharmacology
1107 Immunology
Formatted abstract
The complement system is implicated in the pathogenesis of human inflammatory bowel disease, but the specific role of C5a has never been examined. We have compared the efficacy of an orally active human C5a receptor antagonist (AcPhe[Orn-Pro-D-cyclohexylalanine-Trp-Arg]), prednisolone, and infliximab against trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. The drugs were administered either 2 days before or 24 h after TNBS instillation, and rats were then examined after 8 days. Drug-free colitis control rats showed severe disease pathology with significant mortality (39%). Rats pre or posttreated with the C5a antagonist (10 mg/kg/day peroral, 0.3 mg/kg/day s.c.) had reduced mortality and significantly improved macroscopic scores, colon edema, colon myeloperoxidase levels, reduced concentrations of TNF-α levels in the colon and serum, and had greater food intake resulting in greater weight gains than colitis-only rats. Rats pretreated with prednisolone (1 mg/kg/day s.c.) displayed significant improvement in parameters measured, but posttreatment was ineffective. Single dose pretreatment with the TNF-α inhibitor infliximab (3 mg/kg i.v.) also had significant improvements in the parameters measured. Rats pretreated with a combination of the C5a antagonist and prednisolone showed no greater improvements than either drug alone. These findings suggest a central role for complement, particularly C5a, in the pathology of TNBS-induced colitis in rats, indicating a possible therapeutic role for C5a antagonists in inflammatory bowel disease.
Copyright ©2003 by The American Association of Immunologists, Inc. All rights reserved.
Keyword Immunology
Tumor-necrosis-factor
Acid-induced colitis
Ulcerative-colitis
Crohns-disease
Corticosteroid-therapy
Activated complement
Controlled trial
Animal-models
Factor-alpha
Inhibition
Q-Index Code C1

 
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Created: Wed, 15 Aug 2007, 12:03:16 EST