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Size and surface modification of silica nanoparticles affect the severity of lung toxicity by modulating endosomal ROS generation in macrophages
Particle and Fibre Toxicology ( IF 10 ) Pub Date : 2021-06-17 , DOI: 10.1186/s12989-021-00415-0
Masahide Inoue 1 , Koji Sakamoto 1 , Atsushi Suzuki 1 , Shinya Nakai 2 , Akira Ando 1 , Yukihiko Shiraki 3 , Yoshio Nakahara 1 , Mika Omura 2 , Atsushi Enomoto 3 , Ikuhiko Nakase 2 , Makoto Sawada 4, 5 , Naozumi Hashimoto 1
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As the application of silica nanomaterials continues to expand, increasing chances of its exposure to the human body and potential harm are anticipated. Although the toxicity of silica nanomaterials is assumed to be affected by their physio-chemical properties, including size and surface functionalization, its molecular mechanisms remain unclear. We hypothesized that analysis of intracellular localization of the particles and subsequent intracellular signaling could reveal a novel determinant of inflammatory response against silica particles with different physico-chemical properties. We employed a murine intratracheal instillation model of amorphous silica nanoparticles (NPs) exposure to compare their in vivo toxicities in the respiratory system. Pristine silica-NPs of 50 nm diameters (50 nm-plain) induced airway-centered lung injury with marked neutrophilic infiltration. By contrast, instillation of pristine silica particles of a larger diameter (3 μm; 3 μm-plain) significantly reduced the severity of lung injury and neutrophilic infiltration, possibly through attenuated induction of neutrophil chemotactic chemokines including MIP2. Ex vivo analysis of alveolar macrophages as well as in vitro assessment using RAW264.7 cells revealed a remarkably lower cellular uptake of 3 μm-plain particles compared with 50 nm-plain, which is assumed to be the underlying mechanism of attenuated immune response. The severity of lung injury and neutrophilic infiltration was also significantly reduced after intratracheal instillation of silica NPs with an amine surface modification (50 nm-NH2) when compared with 50 nm-plain. Despite unchanged efficacy in cellular uptake, treatment with 50 nm-NH2 induced a significantly attenuated immune response in RAW264.7 cells. Assessment of intracellular redox signaling revealed increased reactive oxygen species (ROS) in endosomal compartments of RAW264.7 cells treated with 50 nm-plain when compared with vehicle-treated control. In contrast, augmentation of endosomal ROS signals in cells treated with 50 nm-NH2 was significantly lower. Moreover, selective inhibition of NADPH oxidase 2 (NOX2) was sufficient to inhibit endosomal ROS bursts and induction of chemokine expressions in cells treated with silica NPs, suggesting the central role of endosomal ROS generated by NOX2 in the regulation of the inflammatory response in macrophages that endocytosed silica NPs. Our murine model suggested that the pulmonary toxicity of silica NPs depended on their physico-chemical properties through distinct mechanisms. Cellular uptake of larger particles by macrophages decreased, while surface amine modification modulated endosomal ROS signaling via NOX2, both of which are assumed to be involved in mitigating immune response in macrophages and resulting lung injury.

中文翻译:

二氧化硅纳米粒子的尺寸和表面改性通过调节巨噬细胞内体 ROS 的产生来影响肺毒性的严重程度

随着二氧化硅纳米材料的应用不断扩大,预计其暴露于人体和潜在危害的机会会增加。尽管假定二氧化硅纳米材料的毒性受其理化性质(包括尺寸和表面功能化)的影响,但其分子机制仍不清楚。我们假设对颗粒的细胞内定位和随后的细胞内信号传导的分析可以揭示针对具有不同理化特性的二氧化硅颗粒的炎症反应的新决定因素。我们采用了无定形二氧化硅纳米粒子 (NPs) 暴露的小鼠气管内滴注模型来比较它们在呼吸系统中的体内毒性。50 nm 直径(50 nm-plain)的原始二氧化硅-NPs 诱导以气道为中心的肺损伤,并伴有明显的中性粒细胞浸润。相比之下,较大直径(3 μm;3 μm-plain)的原始二氧化硅颗粒的滴注显着降低了肺损伤和中性粒细胞浸润的严重程度,这可能是通过减弱诱导包括 MIP2 在内的中性粒细胞趋化因子来实现的。肺泡巨噬细胞的离体分析以及使用 RAW264.7 细胞的体外评估显示,与 50 nm 平原相比,3 μm 平原颗粒的细胞摄取显着降低,这被认为是减弱免疫反应的潜在机制。与 50 nm-plain 相比,在气管内滴注具有胺表面改性 (50 nm-NH2) 的二氧化硅 NPs 后,肺损伤和中性粒细胞浸润的严重程度也显着降低。尽管细胞摄取的功效没有改变,但用 50 nm-NH2 处理在 RAW264.7 细胞中诱导了显着减弱的免疫反应。对细胞内氧化还原信号的评估显示,与载体处理的对照相比,用 50 nm-plain 处理的 RAW264.7 细胞的内体区室中的活性氧 (ROS) 增加。相比之下,用 50 nm-NH2 处理的细胞中内体 ROS 信号的增强显着降低。此外,选择性抑制 NADPH 氧化酶 2 (NOX2) 足以抑制内体 ROS 爆发和诱导用二氧化硅 NPs 处理的细胞中的趋化因子表达,表明 NOX2 产生的内体 ROS 在调节吞噬二氧化硅 NP 的巨噬细胞炎症反应中的核心作用。我们的小鼠模型表明二氧化硅 NPs 的肺毒性取决于它们通过不同机制的理化特性。巨噬细胞对较大颗粒的细胞摄取减少,而表面胺修饰通过 NOX2 调节内体 ROS 信号传导,这两者都被认为与减轻巨噬细胞的免疫反应和导致的肺损伤有关。
更新日期:2021-06-17
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