期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 168, 期 2, 页码 488-501出版社
WILEY
DOI: 10.1111/j.1476-5381.2012.02183.x
关键词
CD88; complement; anaphylatoxin; C5a; PMX205; DSS; IBD
资金
- Canadian Institutes of Health Research
- Nova Scotia Health Research Foundation
- Crohn's and Colitis Foundation
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 mu g 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据