Nowadays, nanotechnology environmental health and safety (nanoEHS) is gaining attention. We previously found that silica nanoparticles (SiNPs) could induce vascular endothelial damage. However, the subsequent toxicologic response to SiNPs-induced endothelial damage was still largely unknown. In this study, we explored the inflammation–coagulation response and thrombotic effects of SiNPs in endothelial cells and zebrafish embryos. For in vitro study, swollen mitochondria and autophagosome were observed in ultrastructural analysis. The cytoskeleton organization was disrupted by SiNPs in vascular endothelial cells. The release of proinflammatory and procoagulant cytokines including IL-6, IL-8, MCP-1, PECAM-1, TF and vWF, were markedly elevated in a dose-dependent manner. For in vivo study, based on the NOAEL for dosimetry selection, and using two transgenic zebrafish, Tg(mpo:GFP) and Tg(fli-1:EGFP), SiNPs-induced neutrophil-mediated inflammation and impaired vascular endothelial cells. With the dosage higher than NOAEL, SiNPs significantly decreased blood flow and velocity, exhibiting a blood hypercoagulable state in zebrafish embryos. The thrombotic effect was assessed by o-dianisidine staining, showed that an increasing of erythrocyte aggregation occurred in SiNPs-treated zebrafish. Microarray analysis was used to screen the possible genes for inflammation–coagulation response to SiNPs in zebrafish, and the JAK1/TF signaling pathway was further verified by qRT-PCR and Western blot assays. For in-deepth study, il6st was knocked down with specific morpholinos. The whole-mount in situ hybridization and qRT-PCR analysis showed that the expression jak1 and f3b were attenuated in il6st knockdown groups. In summary, our data demonstrated that SiNPs could induce inflammation–coagulation response and thrombotic effects via JAK1/TF signaling pathway.

中文翻译：

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纳米二氧化硅在斑马鱼胚胎中引起的炎症-凝血反应和血栓形成作用

如今，纳米技术环境健康与安全（nanoEHS）受到关注。我们先前发现二氧化硅纳米粒子（SiNPs）可以诱导血管内皮损伤。然而，随后对SiNPs诱导的内皮损伤的毒理学反应仍是未知之数。在这项研究中，我们探讨了内皮细胞和斑马鱼胚胎中SiNP的炎症-凝血反应和血栓形成作用。为了进行体外研究，在超微结构分析中观察到了线粒体和自噬体的肿胀。血管内皮细胞中的SiNP破坏了细胞骨架的组织。包括IL-6，IL-8，MCP-1，PECAM-1，TF和vWF在内的促炎和促凝细胞因子的释放以剂量依赖性方式显着升高。对于体内这项基于NOAEL进行剂量学选择的研究，并使用两种转基因斑马鱼Tg（mpo：GFP）和Tg（fli-1：EGFP），SiNPs诱导的中性粒细胞介导的炎症和受损的血管内皮细胞。当剂量高于NOAEL时，SiNPs显着降低了血流量和速度，在斑马鱼胚胎中表现出血液高凝状态。通过邻联二苯胺染色评估血栓形成作用，表明在用SiNPs处理的斑马鱼中红细胞聚集的增加。微阵列分析被用于筛选可能的斑马鱼对SiNPs炎症-凝血反应的基因，并且qRT-PCR和Western blot分析进一步证实了JAK1 / TF信号通路。对于深入研究，il6st被特定的吗啉代击倒。在整个安装原位杂交和qRT-PCR分析显示，表达JAK1和F3B在被衰减IL6ST敲低的基团。总之，我们的数据表明，SiNPs可以通过JAK1 / TF信号通路诱导炎症反应，凝血反应和血栓形成作用。