From the Laboratory for Clinical Thrombosis and Hemostasis, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, The Netherlands (J.J.P., H.M.S.).
Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, The Netherlands (J.J.P., H.M.S.).
Arterioscler Thromb Vasc Biol. 2019 Jan;39(1):13-24. doi: 10.1161/ATVBAHA.118.311655.
Activation of the blood coagulation cascade leads to fibrin deposition and platelet activation that are required for hemostasis. However, aberrant activation of coagulation can lead to thrombosis. Thrombi can cause tissue ischemia, and fibrin degradation products and activated platelets can enhance inflammation. In addition, coagulation proteases activate cells by cleavage of PARs (protease-activated receptors), including PAR1 and PAR2. Direct oral anticoagulants have recently been developed to specifically inhibit the coagulation proteases FXa (factor Xa) and thrombin. Administration of these inhibitors to wild-type mice can be used to determine the roles of FXa and thrombin in different inflammatory diseases. These results can be compared with the phenotypes of mice with deficiencies of either Par1 (F2r) or Par2 (F2rl1). However, inhibition of coagulation proteases will have effects beyond reducing PAR signaling, and a deficiency of PARs will abolish signaling from all proteases that activate these receptors. We will summarize studies that examine the roles of coagulation proteases, particularly FXa and thrombin, and PARs in different mouse models of inflammatory disease. Targeting FXa and thrombin or PARs may reduce inflammatory diseases in humans.
凝血级联的激活导致纤维蛋白沉积和血小板激活，这是止血所必需的。然而，凝血的异常激活可导致血栓形成。血栓可导致组织缺血，纤维蛋白降解产物和活化的血小板可增强炎症反应。此外，凝血蛋白酶通过切割 PAR（蛋白酶激活受体），包括 PAR1 和 PAR2，来激活细胞。最近开发了直接口服抗凝剂，以专门抑制凝血蛋白酶 FXa（因子 Xa）和凝血酶。将这些抑制剂施用于野生型小鼠可用于确定 FXa 和凝血酶在不同炎症性疾病中的作用。这些结果可以与缺乏 PAR1（F2r）或 PAR2（F2rl1）的小鼠表型进行比较。然而，凝血蛋白酶抑制剂的抑制作用不仅会降低 PAR 信号，而且 PAR 缺乏会使激活这些受体的所有蛋白酶的信号丧失。我们将总结研究凝血蛋白酶，特别是 FXa 和凝血酶以及 PARs 在不同炎症性疾病小鼠模型中的作用。靶向 FXa 和凝血酶或 PARs 可能会减少人类的炎症性疾病。
