The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10

Jain, U., Woodruff, T. M. and Stadnyk, A. W. (2013) The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10. British Journal of Pharmacology, 168 2: 488-501. doi:10.1111/j.1476-5381.2012.02183.x


Author Jain, U.
Woodruff, T. M.
Stadnyk, A. W.
Title The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
1476-5381
Publication date 2013-01-01
Year available 2012
Sub-type Article (original research)
DOI 10.1111/j.1476-5381.2012.02183.x
Open Access Status DOI
Volume 168
Issue 2
Start page 488
End page 501
Total pages 14
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley & Sons
Language eng
Subject 3004 Pharmacology
Abstract BACKGROUND AND PURPOSE
Formatted abstract
Background and Purpose: Anti-complement therapies have not been advanced for treating the inflammatory bowel diseases (IBDs) despite a growing body of evidence that blocking C5a protects against induced colitis in rodents. The purpose of this study was to further build on this evidence by examining the efficacy, mechanism and specificity of a potent, non-competitive and orally active C5a receptor (CD88) antagonist, PMX205, in the dextran sulphate sodium (DSS) model of murine innate colitis.

Experimental Approach: Mice with DSS added to their drinking water were orally administered 100 or 200 μg day -1 PMX205 in prophylactic and therapeutic regimens. Clinical illness, colon histology and local generation of inflammatory mediators were measured to evaluate the impact of PMX205 on disease.

Key Results: PMX205 significantly prevented DSS-induced colon inflammation in both regimens, associated with lower pro-inflammatory cytokine production and nitrotyrosine staining in colon sections. Additionally, the levels of anti-inflammatory cytokines IL-4 and IL-10 were increased. PMX205 had no significant effect on C5a levels. The beneficial effect of PMX205 was seen in two strains of mice of differing sensitivities to DSS inflammation, but was inactive in mice lacking CD88.

Conclusions and Implications: Pharmacological inhibition of C5a activity by PMX205 is efficacious in preventing DSS-induced colitis, providing further evidence that targeting CD88 in IBD patients could be a valuable therapeutic option.
Keyword CD88
Complement
Anaphylatoxin
C5a
PMX205
DSS
IBD
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 20 December 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Biomedical Sciences Publications
 
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