Role of plasma high-molecular-weight-kininogen in the pathogenesis of inflammatory bowel disease (MUC5P.748)

Abstract

Abstract High-molecular-weight kininogen (HK) is a major component of plasma kallikrein-kinin system (KKS), its cleavage products bradykinin and HKa are proinflammatory. Clinical observations have shown that KKS activation and HK cleavage are involved in inflammatory bowel disease (IBD). However, the pathogenic role of HK in IBD have never been characterized using a genetic approach. Our goal is to characterize the role of HK in the pathogenesis of IBD，using HK-deficient (Kng1-/-) mice we recently generated. Dextran sulfate sodium (DSS)-induced colitis in mice were induced by 2.5% (wt/vol) DSS in drinking water for 7 days. Plasma bradykinin level in wild-type (WT) mice was elevated on day 7 (p<0.001). Weight loss index and disease activity index (DAI) of DSS-treated Kng1-/- mice were significantly lower than those of WT mice (p<0.05). Kng1-/- mice had a decrease in colonic cytokines (TNF-α, IL-1β, IL-6 and INF-γ) and myeloperoxidase (MPO) levels (p<0.001). As indicated by H&E staining, Kng1-/- mice exhibited a reduced colonic tissue damage and neutrophil infiltration in colonic lamina propria (p<0.001). Similar with Kng1-/- mice, the mice lacking double bradykinin receptors (B1RB2R-/-) exhibited an amelioration of DSS-induced colitis, including the amelioration of weight loss, DAI, colonic tissue damage, and colonic cytokine levels. This study provides the first genetic evidence demonstrating that HK and its cleavage product bradykinin play a critical role in the pathogenesis of IBD.