The relevance of kinin B 1 receptor upregulation in a mouse model of colitis

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 B 1 receptors in a mouse model of colitis. Experimental approach: Colitis was induced in mice by 2,4,6‐trinitrobenzene sulphonic acid (TNBS), and tissue damage and myeloperoxidase activity were assessed. B 1 receptor induction was analysed by organ bath studies, binding assay and reverse transcription PCR. Key results: TNBS‐induced colitis was associated with tissue damage, neutrophil infiltration and time‐dependent increase of colon B 1 receptor‐mediated contraction, with the maximal response observed at 72 h. The upregulation of the B 1 receptor at this time point was also confirmed by means of binding studies. B 1 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 B 1 receptor antagonist SSR240612, and in B 1 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 B 1 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 B 1 receptors in the pathogenesis of colitis. Therefore, the blockade of kinin B 1 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