Severe Asthma-on-Chip: A Novel In Vitro Platform to Model Viral Induced Exacerbations in Asthma

Abstract

New therapies for severe asthma, particularly treatments which can reduce exacerbations remain a great unmet medical need. Advanced pre-clinical models are needed to further elucidate complex mechanisms that underlie asthma exacerbation for the development of novel therapeutics. Recently, we have developed a 3D microphysiological human Airway Chip containing a fully differentiated mucociliary bronchiolar airway epithelium underlined by a microvascular endothelium which experiences fluid flow1. When infected with human Rhinovirus (HRV), a leading cause of asthma exacerbation in children and adults, the Airway Chip demonstrated induction of a pro-inflammatory response characterized by ciliated cells death, goblet cells hyperplasia and release of cytokines including IFN-α2, IFN-λ1, CXCL10 and CXCL11, as well as recruitment and extravasation across the endothelium of circulating human neutrophils. To recapitulate viral-induced asthma exacerbation and model molecular responses observed in severe asthma, we then infected IL-13-treated Airway Chip with HRV. HRV challenge of IL-13-treated cultures resulted in altered interferon response and increase of neutrophil recruitment when compared with IL-13 or HRV stimulation alone. Neutrophil recruitment could be pharmacologically inhibited by MK-7123, a CXCR2 antagonist (10 μM).