期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 154, 期 6, 页码 1276-1286出版社
WILEY
DOI: 10.1038/bjp.2008.212
关键词
inflammation; kinin B-1 receptor; colitis; 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 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-kappa B activation, inducible nitric oxide synthase (iNOS) or tumour necrosis factor alpha (TNF alpha) 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 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.
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