The relevance of kinin B1 receptor upregulation in a mouse model of colitis.
OBJECTIVE
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.


METHODS
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.


RESULTS
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-kappaB activation, inducible nitric oxide synthase (iNOS) or tumour necrosis factor alpha (TNFalpha) significantly reduced B1 receptor agonist-induced contraction. Similar results were observed in iNOS and TNF receptor 1-knockout mice.


CONCLUSIONS
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.
Department of Pharmacology, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
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D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D003106:Colon / Q000473:pathology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007609:Kallidin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009195:Peroxidase / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D007202:Indicators and Reagents; D016328:NF-kappa B; D043783:Receptor, Bradykinin B1; D014409:Tumor Necrosis Factor-alpha; D007609:Kallidin; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II