Silica nanoparticles induced the pre-thrombotic state in rats via activation of coagulation factor XII and the JNK-NF-κB/AP-1 pathway
Silica nanoparticles induced the pre-thrombotic state in rats via activation of coagulation factor XII and the JNK-NF-κB/AP-1 pathway
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DOI：
10.1039/c5tx00118h
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发表时间：
2015-01-01
影响因子：
2.1
通讯作者：
Sun, Zhiwei
中科院分区：
文献类型：
--
作者：
Jiang, Lizhen;Li, Yanbo;Sun, Zhiwei
二氧化硅纳米颗粒（SiNPs）在药物输送和癌症治疗等医学应用中发挥着至关重要的作用。sinp可以通过所有可能的进入途径转移到血液中。然而，关于SiNPs的血栓前作用和体内血栓前状态机制的研究很少。我们专门研究了连续7天静脉注射SiNPs （52 nm）后Wistar大鼠血小板功能和凝血功能的变化。进行血小板聚集试验、血小板膜糖蛋白结构变化、凝血试验、凝/抗凝及纤溶因子及可能的血栓前状态形成的分子机制。我们的研究结果表明，暴露于SiNP后，血小板聚集率和血小板活化显著增加。凝血时间明显缩短，纤维蛋白原（FIB）含量明显升高。SiNPs诱导的凝血因子和凝血酶-抗凝血酶复合物（TAT）表达持续升高。sinp处理组抗凝血酶III （AT-III）明显降低，组织因子途径抑制剂（TFPI）、组织纤溶酶原激活剂（t-PA）和d -二聚体浓度升高。核因子-的磷酸化。B/p65 （NF-.B/p65）和激活蛋白-1/c-Jun （AP-1/c-Jun）及JNK蛋白水平升高。综上所述，我们的研究结果表明，SiNPs通过血小板活化、凝血系统功能亢进、抗凝和纤溶抵抗之间的相互作用，诱导大鼠高凝和血栓前状态。SiNPs与凝血因子XII （fxii）和JNK-NF-kappa B/AP-1通路之间的直接相互作用可能参与了血栓前状态形成的调控。
Silica nanoparticles (SiNPs) play a vital role in medical applications such as drug delivery and cancer therapy. SiNPs can translocate into the bloodstream through all the possible routes of entry. However, there have been scarce studies on the pre-thrombotic effect of SiNPs and the mechanism of the prethrombotic state in vivo. We specifically focused on the changes of platelet function and blood coagulation in Wistar rats after 7 consecutive days of intravenous injection of SiNPs (52 nm). The platelet aggregation assay, structural changes of platelet membrane glucoproteins, coagulation test, coagulant/anticoagulant and fibrinolytic factors and the possible molecular mechanism of pre-thrombotic state formation were performed. Our results demonstrated a significant increase in platelet aggregation rate and platelet activation after SiNP exposure. The clotting time was significantly shortened while fibrinogen (FIB) contents were increased. There were sustained increases in coagulation factors and thrombin-antithrombin complex (TAT) expression induced by SiNPs. Antithrombin III (AT-III) of the SiNP-treated groups was significantly decreased while the concentrations of the tissue factor pathway inhibitor (TFPI), tissue plasminogen activator (t-PA) and D-dimer were elevated. The phosphorylation of nuclear factor-.B/p65 (NF-.B/p65) and activator protein-1/c-Jun (AP-1/c-Jun) and the protein levels of JNK were increased after SiNP exposure. In summary, our results revealed that SiNPs induced the hypercoagulable and prethrombotic state in rats through the interaction between platelet activation, coagulation system hyperfunction, anti-coagulation and fibrinolytic resistance. Direct interactions between SiNPs and coagulation factor XII (F XII) and the JNK-NF-kappa B/AP-1 pathway might be involved in the regulation of pre-thrombotic state formation.