The mechanism of the sterile inflammatory response in the respiratory tract induced by exposure to sterile particles has not been fully elucidated. The aim of our study is to explore the earlier events in initiating inflammatory response at molecular and cellular level in primary cultured human airway epithelial cells (AEC) exposed to silica particles in order to provide information for earlier diagnosis and prevention of silica particle-induced toxicity as well as possible information on the genesis of silicosis. We isolated primary AEC from three healthy adults and treated them with silica particles at different concentrations for 48 h. We found evidence for silica-induced inflammasome activation by the co-localization of Caspase-1 and NLRP3, as well as increased levels of IL-1β and IL-18. Lactate dehydrogenase and NucGreen analysis proved the occurrence of pyroptosis. High throughput mRNA sequencing showed that the inflammatory response and NF-κB signaling pathways were significantly enriched in gene ontology and Kyoto encyclopedia of genes and genomes analysis, and pyroptosis-related genes were up-regulated. The miR-455-3p and five lncRNAs (LOC105375913, NEAT1, LOC105375181, LOC100506098, and LOC105369370) were verified as key factors related to the mechanism by ceRNA network analysis. LOC105375913 was first discovered to be associated with inflammation in AEC. These data suggest that microcrystalline silica can induce significant inflammation and pyroptosis in human primary AEC through NLRP3 inflammasome pathway and NF-κB signaling pathway at both the gene and protein levels, and the possible mechanism could be miR-455-3p mediated ceRNA hypothesis. Our data provide a method for the studies of the respiratory toxicity of fine particulate matter and the pathogenesis of early silicosis. The miR-455-3p and five lncRNAs related ceRNA network might be the toxicity mechanism of microcrystalline silica particles to AEC.

中文翻译：

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微晶二氧化硅颗粒通过人原代呼吸道上皮细胞焦亡诱导炎症反应

暴露于无菌颗粒引起的呼吸道无菌炎症反应的机制尚未完全阐明。我们研究的目的是探索暴露于二氧化硅颗粒的原代培养的人气道上皮细胞 (AEC) 在分子和细胞水平上引发炎症反应的早期事件，以便为早期诊断和预防二氧化硅颗粒诱导的毒性提供信息以及有关矽肺起源的可能信息。我们从三名健康成人中分离出原发性 AEC，并用不同浓度的二氧化硅颗粒处理 48 小时。我们发现了通过 Caspase-1 和 NLRP3 的共定位以及增加的 IL-1β 和 IL-18 水平来激活二氧化硅诱导的炎症小体的证据。乳酸脱氢酶和NucGreen分析证明了细胞焦亡的发生。高通量 mRNA 测序显示炎症反应和 NF-κB 信号通路在基因本体和京都基因百科全书和基因组分析中显着富集，细胞焦亡相关基因上调。通过 ceRNA 网络分析，miR-455-3p 和五个 lncRNA（LOC105375913、NEAT1、LOC105375181、LOC100506098 和 LOC105369370）被证实为与该机制相关的关键因素。LOC105375913 首次被发现与 AEC 中的炎症有关。这些数据表明，微晶二氧化硅可通过 NLRP3 炎性体通路和 NF-κB 信号通路在基因和蛋白质水平上诱导人原发性 AEC 发生显着炎症和细胞焦亡，可能的机制可能是 miR-455-3p 介导的 ceRNA 假说。我们的数据为细颗粒物的呼吸毒性和早期矽肺发病机制的研究提供了一种方法。miR-455-3p和5个lncRNAs相关的ceRNA网络可能是微晶二氧化硅颗粒对AEC的毒性机制。