Use of EpiAlveolar Lung Model to Predict Fibrotic Potential of Multiwalled Carbon Nanotubes
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/cm2) 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.
EpiAlveolar (ALV-100-FT-PE12), ALV-100-FT-MAC-PE12, lung fibrosis, profibrotic response, human derived macrophages, cytokeratin-19 CK19, vimentin, cytokeratin-8 CK8, prosurfactant C (pSP-C), ZO-1, TEER, TBG-b, fibronectin, Collagen 1, a-smooth muscle actin (a-SMA), TNF-a, IL-1b, Colagane 1a1, silica, LDH, Triton X-100 (0.2%), long term exposure, ATI, ATII (alveolar type 2)
multiwalled carbon nanotuges (MWCNT), DQ12, Nanocyl, Mitsui-7, TGF-b
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