The relevance of kinin B1 receptor upregulation in a mouse model of colitis
Article first published online: 29 JAN 2009
2008 British Pharmacological Society
British Journal of Pharmacology
Volume 154, Issue 6, pages 1276–1286, July 2008
How to Cite
Hara, D. B., Leite, D. F. P., Fernandes, E. S., Passos, G. F., Guimarães, A. O., Pesquero, J. B., Campos, M. M. and Calixto, J. B. (2008), The relevance of kinin B1 receptor upregulation in a mouse model of colitis. British Journal of Pharmacology, 154: 1276–1286. doi: 10.1038/bjp.2008.212
- Issue published online: 29 JAN 2009
- Article first published online: 29 JAN 2009
- (Received February 25, 2008, Revised April 16, 2008, Accepted May 6, 2008)
- kinin B1 receptor;
- pro-inflammatory peptides;
- inflammatory bowel disease treatment
Background and purpose:
Kinins are implicated in many pathophysiological conditions, and recent evidence has suggested their involvement in colitis. This study assessed the role of the kinin B1 receptors in a mouse model of colitis.
Colitis was induced in mice by 2,4,6-trinitrobenzene sulphonic acid (TNBS), and tissue damage and myeloperoxidase activity were assessed. B1 receptor induction was analysed by organ bath studies, binding assay and reverse transcription PCR.
TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of colon B1 receptor-mediated contraction, with the maximal response observed at 72 h. The upregulation of the B1 receptor at this time point was also confirmed by means of binding studies. B1 receptor mRNA levels were elevated as early as 6 h after colitis induction and remained high for up to 48 h. TNBS-evoked tissue damage and neutrophil influx were reduced by the selective B1 receptor antagonist SSR240612, and in B1 receptor knockout mice. In vivo treatment with inhibitors of protein synthesis, nuclear factor-κB activation, inducible nitric oxide synthase (iNOS) or tumour necrosis factor α (TNFα) significantly reduced B1 receptor agonist-induced contraction. Similar results were observed in iNOS and TNF receptor 1-knockout mice.
Conclusions and implications:
These results provide convincing evidence on the role of B1 receptors in the pathogenesis of colitis. Therefore, the blockade of kinin B1 receptors might represent a new therapeutic option for treating inflammatory bowel diseases.
British Journal of Pharmacology (2008) 154, 1276–1286; doi:fn1; published online 9 June 2008