PDF(Pubmed)
Abstract：
A dysregulated plasma contact system is involved in various pathological conditions, such as hereditary angioedema, Alzheimer disease, and sepsis. We previously showed that the 3E8 anti-high molecular weight kininogen (anti-HK) antibody blocks HK cleavage and bradykinin generation in human plasma ex vivo. Here, we show that 3E8 prevented not only HK cleavage but also factor XI (FXI) and prekallikrein (PK) activation by blocking their binding to HK in mouse plasma in vivo. 3E8 also inhibited contact system-induced bradykinin generation in vivo. Interestingly, FXII activation was also inhibited, likely because of the ability of 3E8 to block the positive feedback activation of FXII by kallikrein (PKa). In human plasma, 3E8 also blocked PK and FXI binding to HK and inhibited both thrombotic (FXI activation) and inflammatory pathways (PK activation and HK cleavage) of the plasma contact system activation ex vivo. Moreover, 3E8 blocked PKa binding to HK and dose-dependently inhibited PKa cleavage of HK. Our results reveal a novel strategy to inhibit contact system activation in vivo, which may provide an effective method to treat human diseases involving contact system dysregulation.
摘要：
失调的血浆接触系统涉及各种病理状况，比如遗传性血管性水肿,老年痴呆症,还有败血症.我们先前证明3E8抗HK抗体在人血浆中离体阻断HK裂解和缓激肽生成。在这里，我们显示3E8通过阻断其与小鼠血浆中HK的结合，不仅可以防止HK裂解，而且还可以防止因子XI（FXI）和前激肽释放酶（PK）的激活。3E8还抑制了体内接触系统诱导的缓激肽产生。有趣的是,因子XII（FXII）的激活也被抑制，可能是由于3E8阻断激肽释放酶（PKa）对FXII的正反馈激活的能力。在人类血浆中，3E8还阻断PK和FXI与HK的结合,并抑制血浆接触系统体外活化的血栓形成(FXI活化)和炎症途径(PK活化和HK裂解)。此外，3E8阻断PKa与HK的结合并剂量依赖性地抑制HK的PKa裂解。我们的结果揭示了一种抑制体内接触系统激活的新策略，可以提供一种治疗涉及接触系统失调的人类疾病的有效方法。
