Heat stress-induced disruption of endothelial barrier function is via PAR1 signaling and suppressed by Xuebijing injection.
Heat stress-induced disruption of endothelial barrier function is via PAR1 signaling and suppressed by Xuebijing injection.
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热应激引起的内皮屏障功能破坏是通过 PAR1 信号传导引起的，并被血必净注射液抑制
DOI：
10.1371/journal.pone.0118057
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Su L
中科院分区：
文献类型：
--
作者：
Xu Q;Liu J;Wang Z;Guo X;Zhou G;Liu Y;Huang Q;Su L
血管通透性增加导致急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)是中暑发病机制的核心。凝血酶受体1(PAR1)是凝血酶的受体，在细胞外刺激对内皮屏障功能的破坏中起着关键作用。然而，PAR1在热应激诱导的内皮高通透性中的作用尚不清楚。本研究检测了热应激人脐静脉内皮细胞(HUVECs)中PAR1蛋白的表达，观察了PAR1通过抑制PAR1的siRNA、中和抗体(抗PAR1)、特异性抑制剂(RWJ56110)和治疗败血症的中药血必净注射液(XBJ)对血管内皮细胞通透性、F-肌动蛋白重排和Moesin磷酸化的影响，并通过RWJ56110、抗PAR1和XBJ抑制PAR1在小鼠中暑相关ALI/ARDS中的作用。我们发现，热应激诱导内皮细胞在热应激后2小时表达PAR1蛋白，在热刺激60或120分钟后，内皮细胞释放PAR1的激活剂--内皮基质金属蛋白酶1，并促进内皮高通透性和F-肌动蛋白重排，而RWJ56110、抗PAR1和siRNA抑制PAR1。PAR1介导Moesin的磷酸化，导致F-肌动蛋白重排和内皮屏障功能的破坏。为了证实体外实验的结果，我们发现RWJ56110和抗PAR1显著减少了中暑小鼠的肺水肿、肺微血管通透性、蛋白质渗出和白细胞渗出。此外，在体外和体内热应激模型中，XBJ都被发现抑制PAR1-moesin信号通路，并对维持内皮屏障功能具有保护作用，与上面观察到的抑制PAR1的作用相似。这些结果表明，PAR1是治疗中暑的潜在靶点。
Increased vascular permeability leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is central to the pathogenesis of heatstroke. Protease-activated receptor 1 (PAR1), the receptor for thrombin, plays a key role in disruption of endothelial barrier function in response to extracellular stimuli. However, the role of PAR1 in heat stress-induced endothelial hyper-permeability is unknown. In this study, we measured PAR1 protein expression in heat-stressed human umbilical venous endothelial cells (HUVECs), investigated the influences of PAR1 on endothelial permeability, F-actin rearrangement, and moesin phosphorylation by inhibiting PAR1 with its siRNA, neutralizing antibody (anti-PAR1), specific inhibitor(RWJ56110), and Xuebijing injection (XBJ), a traditional Chinese medicine used for sepsis treatment, and evaluated the role of PAR1 in heatstroke-related ALI/ARDS in mice by suppressing PAR1 with RWJ56110, anti-PAR1and XBJ. We found that heat stress induced PAR1 protein expression 2h after heat stress in endothelial cells, caused the release of endothelial matrix metalloprotease 1, an activator of PAR1, after 60 or 120 min of heat stimulation, as well as promoted endothelial hyper-permeability and F-actin rearrangement, which were inhibited by suppressing PAR1 with RWJ56110, anti-PAR1 and siRNA. PAR1 mediated moesin phosphorylation, which caused F-actin rearrangement and disruption of endothelial barrier function. To corroborate findings from in vitro experiments, we found that RWJ56110 and the anti-PAR1 significantly decreased lung edema, pulmonary microvascular permeability, protein exudation, and leukocytes infiltrations in heatstroke mice. Additionally, XBJ was found to suppress PAR1-moesin signal pathway and confer protective effects on maintaining endothelial barrier function both in vitro and in vivo heat-stressed model, similar to those observed above with the inhibition of PAR1. These results suggest that PAR1 is a potential therapeutic target in heatstroke.
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影响因子：
11.2
作者：
Juncker-Jensen A;Deryugina EI;Rimann I;Zajac E;Kupriyanova TA;Engelholm LH;Quigley JP
通讯作者：
Quigley JP
DOI：
10.1152/ajplung.00200.2013
发表时间：
2014-04-01
影响因子：
4.9
作者：
Pirot, Nelly;Delpech, Helene;Pinet, Valerie
通讯作者：
Pinet, Valerie
影响因子：
9.3
作者：
Wang J;Liu H;Chen B;Li Q;Huang X;Wang L;Guo X;Huang Q
通讯作者：
Huang Q
影响因子：
3.8
作者：
Ng, KY;Cho, CW;Tanguay, RL
通讯作者：
Tanguay, RL
影响因子：
3.1
作者：
Varghese, GM;John, G;Mathai, D
通讯作者：
Mathai, D