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

Abstract

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-kB activation, inducible nitric oxide synthase (iNOS) or tumour necrosis factor a (TNFa) 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.

Kallikrein – Kinin System and Coagulation System in Inflammatory Bowel Diseases

“…The recent experimental study investigated the role of BR1s in TNBS -induced mouse model of colitis showing that that selective, orally active, non -peptide B1R antagonist SSR240612 markedly reduced TNBS -induced colitis e.g. intestinal tissue damage and neutrophil influx (Hara et al, 2008). Importantly this study clarified evidence that TNF -may upregulate B1R expression in TNBS colitis model suggesting that anti-TNF-monoclonal antibodies may in part modulate IBD by regulation of BR1 expression.…”

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…B 1 receptor induction by bacterial lipopolysaccharide (LPS) was inhibited by glucocorticoid pretreatment, cyclooxygenase (COX) blockade, and agents inhibiting the synthesis or action of TNF-␣ (82,84,205,608); moreover, endogenous glucocorticoid hormones were shown to exert a tonic inhibitory control on receptor expression through a NF-B-mediated pathway (78). In a model of experimental colitis in mice, B 1 receptor upregulation depended on de novo protein synthesis, NF-B activation, TNF-␣ production, and inducible NO synthase (iNOS) activity (267). Platelet-activating factor (PAF), a proinflammatory mediator, was shown to upregulate B 1 receptors in the rat skin through a pathway involving neutrophils and a NF-B-TNF-␣-IL-1␤ axis (181, 182).…”

Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

“…13 Specific inflamed organ-induced B1R expression and the availability of an orally active B1R antagonist (B1Ra) has made the B1R a potential therapeutic target for the treatment of pathologies related to chronic inflammation, such as atherosclerosis, airway inflammation, diabetic neuropathy, arthritis, and neuropathic pain. 14,15 Indeed, since the work of Gougat et al 16 describing the selectivity of this orally active B1Ra, a number of original in vivo studies have reported its therapeutic potential in inflammatory bowel disease, 17 skin inflammatory diseases, 18 sensory polyneuropathy, 19 and neuropathic pain. 20 The role of the B1R in renal inflammation has been poorly investigated.…”