Center of Experimental and Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands.
Curr Vasc Pharmacol. 2012 Sep;10(5):632-8. doi: 10.2174/157016112801784549.
Sepsis results in the concurrent activation of inflammatory and procoagulant pathways. Bacterial products and proinflammatory cytokines trigger the coagulation system primarily via induction of tissue factor. During sepsis, activation of coagulation is accompanied by impaired function of major anticoagulant mechanisms, including antithrombin, the protein C system and fibrinolysis. Protease activated receptors (PARs) form the molecular connection between coagulation and inflammation, and especially PAR1 seems to play an eminent role in sepsis pathogenesis. Activated protein C (APC) can cleave PAR1 when associated with either the endothelial protein C receptor (EPCR) or CD11b/CD18, resulting in broad cytoprotective effects mediated by sphingosine 1 phosphate (S1P) receptor 1 (S1P1). In contrast, activation of PAR1 by high dose thrombin results in barrier disruptive effects in endothelial cells via an S1P3 dependent mechanism. Recombinant APC protects against mortality in experimental endotoxemia and sepsis by effects that can be mediated by either EPCR - PAR1 dependent (endothelial cells, dendritic cells) or CD11b/CD18 - PAR1 dependent (macrophages) mechanisms. These protective APC effects do not rely on the anticoagulant properties of this protein. APC mutants that lack anticoagulant properties but retain the capacity to activate PAR1 are promising new drugs for sepsis treatment.
脓毒症会导致炎症和促凝途径的同时激活。细菌产物和促炎细胞因子主要通过诱导组织因子来触发凝血系统。在脓毒症中，凝血的激活伴随着主要抗凝机制（包括抗凝血酶、蛋白 C 系统和纤维蛋白溶解）的功能受损。蛋白酶激活受体 (PARs) 形成了凝血和炎症之间的分子联系，特别是 PAR1 似乎在脓毒症发病机制中起着重要作用。活化蛋白 C (APC) 可以在与内皮蛋白 C 受体 (EPCR) 或 CD11b/CD18 结合时裂解 PAR1，从而导致通过鞘氨醇 1 磷酸 (S1P) 受体 1 (S1P1) 介导的广泛细胞保护作用。相比之下，高剂量凝血酶通过依赖于 S1P3 的机制激活 PAR1 会导致内皮细胞的屏障破坏作用。重组 APC 通过 EPCR-PAR1 依赖（内皮细胞、树突状细胞）或 CD11b/CD18-PAR1 依赖（巨噬细胞）机制发挥作用，可预防实验性内毒素血症和脓毒症的死亡率。这些保护 APC 的作用不依赖于该蛋白的抗凝特性。缺乏抗凝特性但保留激活 PAR1 能力的 APC 突变体是治疗脓毒症的有前途的新药。
