A Micro-Engineered Airway Lung-Chip Models Key Features of Viral-Induced Exacerbation of Asthma

Rationale: Viral-induced exacerbation of asthma are a major cause of hospitalization and mortality. Our understanding of the complex mechanisms underlying asthma exacerbation is hindered by the lack of physiological relevance and cellular complexity of traditional in vitro systems and the limited human translatability of animal models. Objectives: To develop a new micro-engineered model of rhinovirus-induced asthma exacerbation that recapitulates live viral infection of asthmatic airway epithelium, neutrophil transepithelial migration, and enables evaluation of immunomodulatory therapy. Methods: A micro-engineered model of fully differentiated human mucociliary airway epithelium was stimulated with IL-13 to induce a Th2-type asthmatic phenotype and infected with live human rhinovirus 16 (HRV16) to reproduce clinical features of viral-induced asthma exacerbation. Measurements and Main Results: Infection with HRV16 replicated key hallmarks of the cytopathology and inflammatory responses observed in human airways. Generation of a Th2 microenvironment through exogenous IL-13 stimulation induced features of asthmatics airways, including goblet cell hyperplasia, reduction of cilia beating frequency, and endothelial activation, but did not alter rhinovirus infectivity or replication. High resolution kinetic analysis of secreted inflammatory markers revealed that IL-13 treatment altered the IL-6, IFN-gamma1, and CXCL10 secretory phases in response to HRV16. Airway Lung-Chips perfused with human neutrophils demonstrated greatest neutrophil transepithelial migration when viral infection was combined with IL-13 treatment, while treatment with MK-7123, a CXCR2 antagonist, reduced neutrophil diapedesis in all conditions. Conclusions: This micro-engineered Airway Lung-Chip provides a novel human-relevant platform for exploring the complex mechanisms underlying viral-induced asthma exacerbation. Our data suggest that IL-13 may impair the hosts9s ability to mount an appropriate and coordinated immune response to rhinovirus infection. We also show that the Airway Lung-Chip can be used to assess the efficacy of modulators of the immune response.