Lee Wonhwa, Ku Sae-Kwang, Bae Jong-Sup
Jong-Sup Bae, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701, Republic of Korea, Tel.: +82 53 950 8570, Fax: +82 53 950 8557, E-mail:
Thromb Haemost. 2014 Oct;112(4):757-69. doi: 10.1160/TH14-03-0233. Epub 2014 Jul 10.
Nuclear DNA-binding protein high mobility group box 1 (HMGB1) acts as a late mediator of severe vascular inflammatory conditions, such as sepsis. Activated factor X (FXa) is an important player in the coagulation cascade responsible for thrombin generation, and it influences cell signalling in various cell types by activating protease-activated receptors (PARs). However, the effect of FXa on HMGB1-induced inflammatory response has not been studied. First, we addressed this issue by monitoring the effects of post-treatment with FXa on lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated regulation of pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Post-treatment with FXa was found to suppress LPS-mediated release of HMGB1 and HMGB1-mediated cytoskeletal rearrangements. FXa also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice. In addition, FXa inhibited the production of tumour necrosis factor-α and interleukin (IL)-1β. FXa also facilitated the downregulation of CLP-induced release of HMGB1, production of IL-6, and mortality. Collectively, these results suggest that FXa may be regarded as a candidate therapeutic agent for treating vascular inflammatory diseases by inhibiting the HMGB1 signalling pathway.
核DNA结合蛋白高迁移率族蛋白B1（HMGB1）是严重血管炎症性疾病（如脓毒症）的晚期介质。活化的凝血因子X（FXa）是凝血级联反应中负责生成凝血酶的重要因子，它通过激活蛋白酶激活受体（PARs）影响多种细胞类型的细胞信号传导。然而，FXa对HMGB1诱导的炎症反应的影响尚未得到研究。首先，我们通过监测FXa后处理对脂多糖（LPS）和盲肠结扎穿刺（CLP）介导的人脐静脉内皮细胞（HUVECs）和脓毒症小鼠中HMGB1释放以及HMGB1介导的促炎反应调节的影响来解决这个问题。发现FXa后处理可抑制LPS介导的HMGB1释放以及HMGB1介导的细胞骨架重排。FXa还抑制脓毒症小鼠中HMGB1介导的高通透性和白细胞迁移。此外，FXa抑制肿瘤坏死因子-α和白细胞介素（IL）-1β的产生。FXa还促进CLP诱导的HMGB1释放、IL-6产生和死亡率的下调。总体而言，这些结果表明FXa可能被视为通过抑制HMGB1信号通路治疗血管炎性疾病的候选治疗药物。
