Inflammation and the activated protein C anticoagulant pathway

被引:211
作者
Esmon, Charles T.
机构
[1] Oklahoma Med Res Fdn, Cardiovasc Biol Res Program, Oklahoma City, OK 73104 USA
[2] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA
[3] Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73190 USA
[4] Howard Hughes Med Inst, Oklahoma City, OK USA
关键词
protein C; thrombomodulin; thrombin; sepsis; endothelial cell protein C receptor;
D O I
10.1055/s-2006-939554
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
After a coagulation stimulus, the blood clotting cascade amplifies largely unchecked until very high levels of thrombin are generated. Natural anticoagulant mechanisms (for example, the protein C anticoagulant pathway) are amplified to prevent excessive thrombin generation. Thrombin binds to thrombomodulin (TM) and this complex and then activates protein C similar to 1000 times faster than free thrombin. Protein C activation is enhanced similar to 20-fold further by the endothelial cell protein C receptor (EPCR). Activated protein C proteolytically inactivates factor Va (FVa) and FVIIIa, thereby blocking the amplification of the coagulation system, a process that is accelerated by protein S. TM not only accelerates protein C activation, but also decreases endothelial cell activation by blocking high-mobility group protein-B1 inflammatory functions and suppressing both nuclear factor-kappa B nuclear translocation and the mitogen-activated protein kinase pathways. The thrombin-TM complex also activates thrombin-activatable fibrinolysis inhibitor, a procarboxypeptidase that renders fibrin resistant to clot lysis and neutralizes vasoactive molecules Such as complement C5a. Activated protein C has a variety of antiinflammatory activities. It suppresses inflammatory cytokine elevation in animal models of severe sepsis, inhibits leukocyte adhesion, decreases leukocyte chemotaxis, reduces endothelial cell apoptosis, helps maintain endothelial cell barrier function through activation of the sphingosine-1 phosphate receptor, and minimizes the decrease in blood pressure associated with severe sepsis. Most of these functions are dependent on binding to EPCR. Overall this pathway is critical to both regulation of the blood coagulation process, and control of the innate inflammatory response and some of its associated downstream pathologies.
引用
收藏
页码:49 / 60
页数:12
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