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Yi Wu, P-143 YI High-Molecular-Weight-Kininogen and Bradykinin Are Critical for the Pathogenesis of Inflammatory Bowel Disease, Inflammatory Bowel Diseases, Volume 22, Issue suppl_1, March 2016, Pages S53–S54, https://doi.org/10.1097/01.MIB.0000480276.22000.61
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High-molecular-weight kininogen (HK) is a major component of plasma kallikrein-kinin system (KKS). Upon activation of the KKS, the cleavage products of HK, bradykinin and HKa are produced. The in vitro studies have shown that both bradykinin and HKa are proinflammatory. Clinical observations have indicated that the activation of KKS and HK cleavage exists in patients with inflammatory bowel disease (IBD). However, the role of HK in the pathogenesis of IBD has never been characterized using a genetic approach.
We characterized the role of HK and bradykinin in the pathogenesis of IBD and the underlying mechanisms using HK-deficient (Kng1−/−) and bradykinin receptor deficient mice, in a dextran sulfate sodium (DSS)-induced colitis model. Mice were treated with 2.5% (wt/vol) DSS in drinking water for 7 days.
Plasma level of bradykinin in wild-type (WT) mice was elevated on day 7 in DSS-induced colitis (P < 0.001), suggesting the activation of the KKS in this model. Weight loss index and disease activity index (DAI) of DSS-treated HK-deficient (Kng1−/−) mice were significantly lower than those of WT mice (P < 0.05). As detected by H&E staining, colonic tissue damage in Kng1−/− mice was ameliorated compared with that of WT mice. Moreover, Kng1−/− mice exhibited a decrease in colonic cytokines (TNF-α, IL-1β, IL-6, INF-γ) and myeloperoxidase (MPO) level (P < 0.001). Neutrophil infiltration in colonic lamina propria was also reduced in Kng1−/− mice (P < 0.001). Furthermore, the mice lacking double bradykinin receptors (B1RB2R−/−) also exhibited a reduced DSS-induced colitis, including amelioration of weight loss, DAI, colonic tissue damage, and colonic cytokine levels.
Our results demonstrate that HK and its cleavage product bradykinin play a critical role in the pathogenesis of IBD.
- cytokine
- tumor necrosis factors
- weight reduction
- inflammatory bowel disease
- colitis
- dextran sulfate
- kallikrein-kinin system
- kininogen, high-molecular-weight
- neutrophil infiltration
- peroxidase
- plasma
- bradykinin receptor
- bradykinin
- colon
- genetics
- interleukin-6
- mice
- sodium
- cytokinesis
- in vitro study
- lamina propria
- tissue damage
- potable water
