Barosova H1, Maione AG2, Septiadi D1, Sharma M3, Haeni L1, Balog S1, O'Connell O2, Jackson GR2, Brown D4, Clippinger AJ3, Hayden P2,5, Petri-Fink A1,6, Stone V4, Rothen-Rutishauser B1.
1 Adolphe Merkle Institute, University of Fribourg, Chemin des Verdiers 4, 1700 Fribourg, Switzerland.
2 MatTek Corporation, 200 Homer Avenue, Ashland, Massachusetts 01721, United States.
3 PETA International Science Consortium Ltd., 8 All Saints Street, London N1 9RL, U.K.
4 Nano-Safety Research Group, Heriot-Watt University, Edinburgh EH14 4AS, U.K.
5 BioSurfaces, Inc., 200 Homer Ave, Ashland, Massachusetts 01721, United States.
6 Department of Chemistry, University of Fribourg, Chemin du Musée 9, 1700 Fribourg, Switzerland.
This study characterizes a 3D in vitro alveolar tissue model comprised entirely of primary human cells to investigate its ability to predict pulmonary ﬁbrosis. The study demonstrated that the EpiAlveolar model recapitulates relevant lung phenotypes and functions and is stable at VITROCELL Cloud with repeated exposures over 3 weeks.
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.