Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease
Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease
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DOI：
10.1182/blood-2013-08-523936
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发表时间：
2014-03-13
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：
Sparkenbaugh, Erica M.;Chantrathammachart, Pichika;Pawlinski, Rafal
凝血激活和血管炎症是镰状细胞病（SCD）的显著特征。在此之前，我们已经证明，在SCD小鼠模型中，组织因子（TF）的抑制可以减弱凝血和血管炎症的激活。在这项研究中，我们研究了凝血蛋白酶增强镰状BERK小鼠血管炎症的机制。为了专门研究FXa和凝血酶的作用，分别给小鼠喂食含有利伐沙班或达比加群的食物。此外，我们利用骨髓移植培养了在非造血细胞上缺乏蛋白酶活化受体-1 （PAR-1）或蛋白酶活化受体-2 （PAR-2）的镰状小鼠。通过血浆白细胞介素-6 （IL-6）水平测量，非造血细胞中FXa抑制和PAR-2缺乏可减轻全身炎症。相反，凝血酶抑制和非造血细胞PAR-1缺乏都不会影响镰状小鼠血浆中IL-6的水平。然而，凝血酶确实有助于肺中性粒细胞浸润，独立于非造血细胞表达的PAR-1。此外，镰状小鼠血浆中可溶性血管细胞粘附分子-1水平的tgf依赖性增加不是由FXa或凝血酶介导的。我们的数据表明，在SCD小鼠模型中，TF、FXa和凝血酶对血管炎症的影响是不同的。
Activation of coagulation and vascular inflammation are prominent features of sickle cell disease (SCD). Previously, we have shown that inhibition of tissue factor (TF) attenuates activation of coagulation and vascular inflammation in mouse models of SCD. In this study, we examined the mechanism by which coagulation proteases enhance vascular inflammation in sickle BERK mice. To specifically investigate the contribution of FXa and thrombin, mice were fed chow containing either rivaroxaban or dabigatran, respectively. In addition, we used bone marrow transplantation to generate sickle mice deficient in either protease activated receptor-1 (PAR-1) or protease activated receptor-2 (PAR-2) on nonhematopoietic cells. FXa inhibition and PAR-2 deficiency in nonhematopoietic cells attenuated systemic inflammation, measured by plasma levels of interleukin-6 (IL-6). In contrast, neither thrombin inhibition nor PAR-1 deficiency in nonhematopoietic cells affected plasma levels of IL-6 in sickle mice. However, thrombin did contribute to neutrophil infiltration in the lung, independently of PAR-1 expressed by nonhematopoietic cells. Furthermore, the TF-dependent increase in plasma levels of soluble vascular cell adhesion molecule-1 in sickle mice was not mediated by FXa or thrombin. Our data indicate that TF, FXa, and thrombin differentially contribute to vascular inflammation in a mouse model of SCD.