Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Biochim Biophys Acta Mol Cell Res. 2017 Nov;1864(11 Pt B):2118-2127. doi: 10.1016/j.bbamcr.2017.07.009. Epub 2017 Jul 23.
The contact system is a potent procoagulant and proinflammatory plasma protease cascade that is initiated by binding ("contact")-induced, auto-activation of factor XII zymogen. Formed active serine protease FXIIa then cleaves plasma prekallikrein to kallikrein that in turn liberates the mediator bradykinin from its precursor high molecular weight kininogen. Bradykinin induces inflammation with implications for host defense and innate immunity. FXIIa also triggers the intrinsic pathway of coagulation that has been shown to critically contribute to thrombosis. Vice versa, FXII deficiency impairs thrombosis in animal models without inducing abnormal excessive bleeding. Recent work has established the FXIIa-driven contact system as promising target for anticoagulant and anti-inflammatory drugs. This review focuses on the biochemistry of the contact system, its regulation by endogenous and exogenous inhibitors, and roles in disease states. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
接触系统是一个有效的促凝和促炎血浆蛋白酶级联反应，它通过结合（“接触”）诱导的因子 XII 原酶的自动激活而启动。形成的活性丝氨酸蛋白酶 FXIIa 然后裂解血浆激肽原酶为激肽释放酶，激肽释放酶反过来从其前体高分子量激肽原中释放介质缓激肽。缓激肽通过宿主防御和先天免疫的影响引起炎症。FXIIa 还触发已被证明对血栓形成有重要贡献的凝血的固有途径。相反，FXII 缺乏症在不引起异常过度出血的情况下损害动物模型中的血栓形成。最近的工作已经确定 FXIIa 驱动的接触系统是抗凝和抗炎药物的有前途的靶标。这篇综述重点介绍了接触系统的生物化学，其受内源性和外源性抑制剂的调节，以及在疾病状态中的作用。本文是由 Stefan Rose-John 编辑的题为“蛋白水解作用作为病理生理学中的调节事件”的特刊的一部分。
