The present study aimed to evaluate the potential differences in the biological effects of two types of spherical silver particles of 20 and 200 nm (Ag20 and Ag200), and of PVP-coated silver nanowires (AgNWs) with a diameter of 50 nm and length up to 50 μm, using a complex 3D model representative for the alveolar barrier cultured at air-liquid interface (ALI). The alveolar model was exposed to 0.05, 0.5 and 5 μg/cm2 of test compounds at ALI using a state-of-the-art exposure system (Vitrocell™Cloud System). Endpoints related to the oxidative stress induction, anti-oxidant defence mechanisms, pro-inflammatory responses and cellular death were selected to evaluate the biocompatibility of silver particles and nanowires (AgNMs) and to further ascribe particular biological effects to the different morphologic properties between the three types of AgNMs evaluated. Significant cytotoxic effect was observed for all three types of AgNMs at the highest tested doses. The increased mRNA levels of the pro-apoptotic gene CASP7 suggests that apoptosis may occur after exposure to AgNWs. All three types of AgNMs increased the mRNA level of the anti-oxidant enzyme HMOX-1 and of the metal-binding anti-oxidant metallothioneins (MTs), with AgNWs being the most potent inducer. Even though all types of AgNMs induced the nuclear translocation of NF-kB, only AgNWs increased the mRNA level of pro-inflammatory mediators. The pro-inflammatory response elicited by AgNWs was further confirmed by the increased secretion of the 10 evaluated interleukins. In the current study, we demonstrated that the direct exposure of a complex tetra-culture alveolar model to different types of AgNMs at ALI induces shape- and size-specific biological responses. From the three AgNMs tested, AgNWs were the most potent in inducing biological alterations. Starting from 50 ng/cm2, a dose representative for an acute exposure in a high exposure occupational setting, AgNWs induced prominent changes indicative for a pro-inflammatory response. Even though the acute responses towards a dose representative for a full-lifetime exposure were also evaluated, chronic exposure scenarios at low dose are still unquestionably needed to reveal the human health impact of AgNMs during realistic conditions.

中文翻译：

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代表气液界面肺泡屏障的 3D-tetraculture 体外暴露于银颗粒和纳米线

本研究旨在评估两种类型的 20 和 200 nm 球形银颗粒（Ag20 和 Ag200）以及直径为 50 nm 和长度的 PVP 涂层银纳米线（AgNW）的生物效应的潜在差异。至 50 μm，使用代表气液界面 (ALI) 培养的肺泡屏障的复杂 3D 模型。在 ALI 上，使用最先进的暴露系统（Vitrocell™Cloud 系统）将肺泡模型暴露于 0.05、0.5 和 5 μg/cm2 的测试化合物。选择与氧化应激诱导、抗氧化防御机制、促炎症反应和细胞死亡相关的终点来评估银颗粒和纳米线（AgNM）的生物相容性，并进一步将特定的生物效应归因于三者之间的不同形态特性评估的 AgNM 类型。在最高测试剂量下，所有三种类型的 AgNM 均观察到显着的细胞毒性作用。促凋亡基因 CASP7 的 mRNA 水平增加表明暴露于 AgNW 后可能发生细胞凋亡。所有三种类型的 AgNM 都能增加抗氧化酶 HMOX-1 和金属结合抗氧化金属硫蛋白 (MT) 的 mRNA 水平，其中 AgNW 是最有效的诱导剂。尽管所有类型的 AgNM 都会诱导 NF-kB 的核转位，但只有 AgNW 会增加促炎介质的 mRNA 水平。10 种评估的白细胞介素分泌增加进一步证实了 AgNW 引发的促炎反应。在当前的研究中，我们证明了复杂的四培养肺泡模型在 ALI 处直接暴露于不同类型的 AgNM 会诱导形状和大小特异性的生物反应。在测试的三种 AgNM 中，AgNW 诱导生物改变的能力最强。从 50 ng/cm2（高暴露职业环境中急性暴露的代表剂量）开始，AgNW 诱导了表明促炎症反应的显着变化。尽管还评估了对代表一生暴露的剂量的急性反应，但毫无疑问仍然需要低剂量的慢性暴露场景来揭示 AgNM 在现实条件下对人类健康的影响。