In vivo imaging visualizes discoid platelet aggregations without endothelium disruption and implicates contribution of inflammatory cytokine and integrin signaling
In vivo imaging visualizes discoid platelet aggregations without endothelium disruption and implicates contribution of inflammatory cytokine and integrin signaling
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DOI：
10.1182/blood-2011-09-381400
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发表时间：
2012-02-23
期刊：
影响因子：
20.3
通讯作者：
Nagai, Ryozo
中科院分区：
文献类型：
--
作者：
Nishimura, Satoshi;Manabe, Ichiro;Nagai, Ryozo
血栓性血管闭塞独立于斑块发展或内皮细胞（EC）破坏发生的机制尚不清楚，主要是因为无法实时观察血栓的形成，特别是在单血小板水平。在这里，我们证明了由盘状血小板组成的快速形成的血栓可以在活小鼠的肠系膜毛细血管、小动脉和大动脉中诱导形成，从而能够表征血栓形成的动力学和血栓形成过程中的多细胞相互关系。中等功率激光诱导的活性氧（ROS）光化学诱导的血小板聚集无EC破坏。炎症细胞因子tnf - α和IL-1可能是EC反应的关键组成部分，通过调节VWF向细胞表面的动员而起作用。在我们的模型中，血小板GPIb α与内皮VWF结合引发血栓形成，这种作用被ROS清除剂n -乙酰半胱氨酸抑制。血小板中肌动蛋白连接子依赖于α - β 3整合素或Rac1的激活是后期血栓稳定所必需的。我们的新成像技术阐明了盘状血小板在未中断的内皮细胞上炎症性血栓形成的分子机制，并表明控制ROS可能是预防血栓性疾病的有用治疗靶点。（血液杂志；2012;119(8):e45-e56）
The mechanism by which thrombotic vessel occlusion occurs independently of plaque development or endothelial cell (EC) disruption remains unclear, largely because of an inability to visualize the formation of thrombus, especially at the single-platelet level in real time. Here we demonstrate that rapidly developing thrombi composed of discoid platelets can be induced in the mesenteric capillaries, arterioles, and large-sized arteries of living mice, enabling characterization of the kinetics of thrombosis initiation and the multicellular interrelationships during thrombus development. Platelet aggregation without EC disruption was triggered by reactive oxygen species (ROS) photo-chemically induced by moderate power laser irradiation. The inflammatory cytokines TNF-alpha and IL-1 could be key components of the EC response, acting through regulation of VWF mobilization to the cell surface. Thrombus formation was then initiated by the binding of platelet GPIb alpha to endothelial VWF in our model, and this effect was inhibited by the ROS scavenger N-acetylcysteine. Actin linker talin-dependent activation of alphaIIb-beta3 integrin or Rac1 in platelets was required for late-phase thrombus stability. Our novel imaging technology illustrates the molecular mechanism underlying inflammation-based thrombus formation by discoid platelets on undisrupted ECs and suggests control of ROS could be a useful therapeutic target for the prevention of thrombotic diseases. (Blood. 2012; 119(8): e45-e56)