Tissue factor promotes activation of coagulation and inflammation in a mouse model of sickle cell disease
Tissue factor promotes activation of coagulation and inflammation in a mouse model of sickle cell disease
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DOI：
10.1182/blood-2012-04-424143
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发表时间：
2012-07-19
期刊：
影响因子：
20.3
通讯作者：
Pawlinski, Rafal
中科院分区：
文献类型：
--
作者：
Chantrathammachart, Pichika;Mackman, Nigel;Pawlinski, Rafal
镰状细胞病（SCD）与复杂的血管病理生理学有关，包括凝血和炎症的激活。然而，SCD中这两个系统之间的串扰尚未被研究。在这里，我们研究了组织因子（TF）在2种不同的SCD小鼠模型（BERK和Townes）中激活凝血和炎症的作用。BERK小鼠白细胞表达TF蛋白，TF活性较对照组明显升高。我们发现，抑制性抗TF抗体废除凝血激活，但对溶血或贫血没有影响。重要的是，TF的抑制也减弱炎症和内皮细胞损伤，如通过降低IL-6、血清淀粉样蛋白P和可溶性血管细胞粘附分子-1的血浆水平所证明的。此外，我们还发现在用抗TF抗体治疗的镰状细胞小鼠的肺中，趋化因子MCP-1和KC以及髓过氧化物酶的水平降低。最后，我们发现内皮细胞特异性TF缺失对凝血没有影响，但选择性地减弱了IL-6的血浆水平。我们的数据表明，不同细胞来源的TF有助于激活凝血，血管炎症和内皮细胞损伤。此外，似乎TF有助于这些过程而不影响血管内溶血。（血。2012;120（3）：636-646）
Sickle cell disease (SCD) is associated with a complex vascular pathophysiology that includes activation of coagulation and inflammation. However, the crosstalk between these 2 systems in SCD has not been investigated. Here, we examined the role of tissue factor (TF) in the activation of coagulation and inflammation in 2 different mouse models of SCD (BERK and Townes). Leukocytes isolated from BERK mice expressed TF protein and had increased TF activity compared with con-trol mice. We found that an inhibitory anti-TF antibody abrogated the activation of coagulation but had no effect on hemolysis or anemia. Importantly, inhibition of TF also attenuated inflammation and endothelial cell injury as demonstrated by reduced plasma levels of IL-6, serum amyloid P, and soluble vascular cell adhesion molecule-1. In addition, we found decreased levels of the chemokines MCP-1 and KC, as well as myeloperoxidase in the lungs of sickle cell mice treated with the anti-TF antibody. Finally, we found that endothelial cell-specific deletion of TF had no effect on coagulation but selectively attenuated plasma levels of IL-6. Our data indicate that different cellular sources of TF contribute to activation of coagulation, vascular inflammation, and endothelial cell injury. Furthermore, it appears that TF contributes to these processes without affecting intravascular hemolysis. (Blood. 2012;120(3):636-646)