Adolphe Merkle Institute, University of Fribourg, Chemin des Verdiers 4, 1700 Fribourg, Switzerland.
MatTek Corporation, 200 Homer Avenue, Ashland, Massachusetts 01721, United States.
ACS Nano. 2020 Apr 28;14(4):3941-3956. doi: 10.1021/acsnano.9b06860. Epub 2020 Mar 20.
Expansion in production and commercial use of nanomaterials increases the potential human exposure during the lifecycle of these materials (production, use, and disposal). Inhalation is a primary route of exposure to nanomaterials; therefore it is critical to assess their potential respiratory hazard. Herein, we developed a three-dimensional alveolar model (EpiAlveolar) consisting of human primary alveolar epithelial cells, fibroblasts, and endothelial cells, with or without macrophages for predicting long-term responses to aerosols. Following thorough characterization of the model, proinflammatory and profibrotic responses based on the adverse outcome pathway concept for lung fibrosis were assessed upon repeated subchronic exposures (up to 21 days) to two types of multiwalled carbon nanotubes (MWCNTs) and silica quartz particles. We simulate occupational exposure doses for the MWCNTs (1-30 μg/cm) using an air-liquid interface exposure device (VITROCELL Cloud) with repeated exposures over 3 weeks. Specific key events leading to lung fibrosis, such as barrier integrity and release of proinflammatory and profibrotic markers, show the responsiveness of the model. Nanocyl induced, in general, a less pronounced reaction than Mitsui-7, and the cultures with human monocyte-derived macrophages (MDMs) showed the proinflammatory response at later time points than those without MDMs. In conclusion, we present a robust alveolar model to predict inflammatory and fibrotic responses upon exposure to MWCNTs.
随着纳米材料在生产和商业中的应用不断扩大，这些材料在其生命周期（生产、使用和处置）中对人类的潜在暴露也随之增加。吸入是纳米材料暴露的主要途径；因此，评估其潜在的呼吸危害至关重要。在此，我们开发了一种由人原代肺泡上皮细胞、成纤维细胞和内皮细胞组成的三维肺泡模型（EpiAlveolar），该模型可以选择或不选择巨噬细胞，用于预测对气溶胶的长期反应。在对模型进行了彻底的特征描述之后，根据肺纤维化的不良结局途径概念，评估了两种类型的多壁碳纳米管（MWCNT）和石英颗粒在反复亚慢性暴露（长达 21 天）后的促炎和促纤维化反应。我们使用气液界面暴露装置（VITROCELL Cloud）模拟了 MWCNT 的职业暴露剂量（1-30 μg/cm），通过 3 周的重复暴露进行模拟。导致肺纤维化的特定关键事件，如屏障完整性和促炎和促纤维化标志物的释放，显示了该模型的反应性。一般来说，Nanocyl 引起的反应不如 Mitsui-7 明显，且有人类单核细胞衍生的巨噬细胞（MDM）的培养物比没有 MDM 的培养物在稍后的时间点显示出促炎反应。总之，我们提出了一种稳健的肺泡模型，可预测暴露于 MWCNT 后的炎症和纤维化反应。
