Particulate Toxicology in the 21st Century: Organotypic Models Reveal Trans-Epithelial Effects of Particulates in the Respiratory Tract
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Complex multi-cellular in vitro models of the human respiratory tract have provided novel opportunities to advance our understanding of the effects of inhaled particulate exposures on human health. These “organotypic” cell culture models also provide new opportunities to evaluate the impact of inter-individual variability and susceptibility/vulnerability factors on exposure outcomes, and the potential to increasing both the physiological relevance and throughput of particulate toxicology research and testing. This presentation will provide a brief introduction to organotypic multi-cellular in vitro models, examples of how we have used them to characterize the effects of model particulate exposures, and critical considerations for their future use in particulate toxicology. Specifically, data will be presented demonstrating that exposure of a bronchial epithelial barrier to diesel exhaust particulates causes redox imbalance, NRF2 activation, and oxidative stress in underlying lung fibroblasts (i.e., “trans-epithelial” effects) in a multi-cellular model of the tracheobronchial epithelium. The presentation will also describe our development of a novel tri-culture model of the alveolar-microvascular interface and the subsequent demonstration that exposure of an alveolar epithelial barrier induces trans-alveolar oxidative stress and interleukin (IL)-8 release in microvascular endothelial cells. Data will also be presented demonstrating that NRF2-dependent IL-8 secretion from the lung microvascular endothelium is dependent on the activation of mitogen activated protein (MAP) kinases in the adjacent alveolar epithelial barrier. Finally, data regarding the inter-individual variability in in vivo-relevant in vitro assay endpoints and the effect of dosing air-liquid interface differentiated cells by liquid application on common toxicological endpoints and global transcriptional programming will be discussed in the context of the application of organotypic in vitro models in particulate toxicology. Overall, this presentation will provide key examples of how organotypic models of the human respiratory tract can be used to revolutionize our understanding of the cellular and molecular mediators of particulate-induced health effects while also providing a high(er) throughput platform for inhaled particulate screening, testing, and risk assessment.