Tissue factor, coagulation proteases, and protease-activated receptors in endotoxemia and sepsis
Tissue factor, coagulation proteases, and protease-activated receptors in endotoxemia and sepsis
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DOI：
10.1097/01.ccm.0000128445.95144.b8
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发表时间：
2004-05-01
影响因子：
8.8
通讯作者：
Mackman, N
中科院分区：
文献类型：
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作者：
Pawlinski, R;Mackman, N
抑制组织因子-Vila复合体可以减少内毒素血症和败血症动物模型以及严重脓毒症患者的凝血和炎症。然而，组织因子依赖的凝血级联激活增强炎症的机制尚不清楚。我们验证了凝血酶通过激活血管内的蛋白水解酶激活受体(PARs)来增强内毒素血症炎症的假说。我们发现，与对照小鼠相比，表达低水平组织因子的转基因小鼠在内毒素血症小鼠模型中表现出白细胞介素6表达减少和存活率增加。相反，水飞蓟素抑制凝血酶或PAR-1或PAR-2的缺陷并不影响白细胞介素6的表达或死亡率。然而，在PAR-2缺乏的情况下，联合水飞蓟素治疗通过PAR-1和PAR-4抑制凝血酶信号转导减少了内毒素诱导的白细胞介素6的表达，并提高了存活率。综上所述，我们的结果表明，凝血酶激活多个PARs可增强内毒素血症时的炎症反应。
Inhibition of the tissue factor-factor Vila complex reduces coagulation and inflammation in animal models of endotoxemia and sepsis and in patients with severe sepsis. However, the mechanism by which tissue factor-dependent activation of the coagulation cascade enhances inflammation is not known. We tested the hypothesis that coagulation proteases enhance inflammation during endotoxemia by activating protease-activated receptors (PARS) within the vasculature. We found that genetically modified mice expressing low levels of tissue factor exhibited reduced interleukin-6 expression and increased survival in a mouse model of endotoxemia compared with control mice. In contrast, hirudin inhibition of thrombin or a deficiency in either PAR-1 or PAR-2 did not affect interleukin-6 expression or mortality. However, combining hirudin treatment to inhibit thrombin signaling through PAR-1 and PAR-4 with PAR-2 deficiency reduced lipopolysaccharide-induced interleukin-6 expression and increased survival. Taken together, our results suggest that activation of multiple PARS by coagulation proteases enhances inflammation during endotoxemia.