Repeated exposure to aerosolized graphene oxide mediates autophagy inhibition and inflammation in a three-dimensional human airway model. (March 2020)

• Record Type: Journal Article
• Authors: Di Cristo, L.; Grimaldi, B.; Catelani, T.; Vázquez, E.; Pompa, P.P.; Sabella, S.
• Is Part Of: Materials today bio. Volume 6(2020)
• Publication Date: 2020-03
• Subjects: 3D airway model -- Occupational exposure limits -- Repeated exposure -- Aerosol system -- Working lifetime exposure; Materials science -- Periodicals; Biomedical engineering -- Periodicals; Biomedical materials -- Periodicals; 620.1
• DOI: 10.1016/j.mtbio.2020.100050
• Languages: English
• ISSNs: 2590-0064

Abstract

Abstract: Hazard evaluation of engineered nanomaterials (ENMs) using real-world exposure scenario could provide better interpretation of toxicity end points for their use in the assessment of human safety and for their implications in many fields such as toxicology, nanomedicine, and so forth. However, most of the current studies, both in vivo and in vitro, do not reflect realistic conditions of human exposure to ENMs, due to the high doses implemented. Moreover, the use of cellular models cultured under submerged conditions limits their physiological relevance for lung exposure, where cells are primarily cultured at the air-liquid interface. Addressing such issues is even more challenging for emergent nanomaterials, such as graphene oxide (GO), for which little or no information on exposure is available. In this work, we studied the impact of repeated exposure of GO on a three-dimensional (3D) reconstruct of human bronchial tissue, using a nebulizer system focusing on short-term effects. The selected doses (reaching a maximum of ca. 20 ​μg/cm 2 for a period of 4 weeks of exposure) were extrapolated from alveolar mass deposition values of a broader class of carbon-based nanomaterials, reflecting a full working lifetime of human exposure. Experimental results did not show strong toxic effects of GO in terms of viability and integrity of the lung tissue. However, since 2 weeks of treatment, repeated GO exposure elicited a proinflammatory response, moderate barrier impairment, and autophagosome accumulation, a process resulting from blockade of autophagy flux. Interestingly, the 3D airway model could recover such an effect by restoring autophagy flux at longer exposure (30 days). These findings indicate that prolonged exposure to GO produces a time window (during the 30 days of treatment set for this study) for which GO-mediated autophagy inhibition along with inflammation may potentially increase the susceptibility of exposed humans to pulmonary infections and/or lung diseases. This study also highlights the importance of using physiologically relevant in vitro models and doses derived from real-world exposure to obtain focused data for the assessment of human safety. Graphical abstract: A 3D airway model exposed repeatedly to GO for 4 weeks using doses reflecting a potential full working lifetime human exposition. Results show that exposure to inhaled GO triggered a weak proinflammatory response, impairment of barrier integrity, and autophagy blockage, thus potentially increasing susceptibility of exposed workers to pulmonary infections and/or lung diseases. Overall, the presented results highlight the importance of using physiologically relevant in vitro airway models and real-world exposure scenario to predict the impact of exposure to inhaled particles for human safety. Image 1