A potent human C5a receptor antagonist protects against disease pathology in a rat model of inflammatory bowel disease.
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-alpha 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-alpha 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.
Woodruff
Trent M
TM
Department of Physiology and Pharmacology, School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
Arumugam
Thiruma V
TV
Shiels
Ian A
IA
Reid
Robert C
RC
Fairlie
David P
DP
Taylor
Stephen M
SM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects / Q000276:immunology; D003106:Colon / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects / Q000276:immunology; D004487:Edema / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000401:mortality / Q000473:pathology* / Q000517:prevention & control*; D000069285:Infliximab; D008297:Male; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011239:Prednisolone / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors* / Q000502:physiology; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism
C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D000911:Antibodies, Monoclonal; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D011239:Prednisolone; D000069285:Infliximab; D009195:Peroxidase