02975nas a2200349   4500000000100000008004100001260001200042653002100054653002400075653002000099653001800119653001500137100002100152700002200173700001600195700002000211700001800231700001700249700001900266700001800285700001700303700001800320700002600338700001900364700001900383245009900402856006100501300001200562490000700574520203000581022001402611       2020                            d  c2020-1110aairway lung-chip10aasthma exacerbation10aimmune response10aorgan-on-chip10arhinovirus1 aJanna C. Nawroth1 aCarolina Lucchesi1 aDeion Cheng1 aAbhishek Shukla1 aJustin Ngyuen1 aTanvi Shroff1 aAntonio Varone1 aKatia Karalis1 aHyun-Hee Lee1 aStephen Alves1 aGeraldine A. Hamilton1 aMichael Salmon1 aRemi Villenave00aA Microengineered Airway Lung Chip Models Key Features of Viral-induced Exacerbation of Asthma  uhttps://www.atsjournals.org/doi/10.1165/rcmb.2020-0010MA  a591-6000 v633 aViral-induced exacerbation of asthma remains a major cause of hospitalization and mortality. New human-relevant models of the airways are urgently needed to understand how respiratory infections may trigger asthma attacks and to advance treatment development. Here, we describe a new human-relevant model of rhinovirus-induced asthma exacerbation that recapitulates viral infection of asthmatic airway epithelium and neutrophil transepithelial migration, and enables evaluation of immunomodulatory therapy. Specifically, a microengineered model of fully differentiated human mucociliary airway epithelium was stimulated with IL-13 to induce a T-helper cell type 2 asthmatic phenotype and infected with live human rhinovirus 16 (HRV16) to reproduce key features of viral-induced asthma exacerbation. We observed that the infection with HRV16 replicated key hallmarks of the cytopathology and inflammatory responses observed in human airways. Generation of a T-helper cell type 2 microenvironment through exogenous IL-13 stimulation induced features of asthmatic 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 IL-6, IFN-λ1, and CXCL10 secretion in response to HRV16. Neutrophil transepithelial migration was greatest when viral infection was combined with IL-13 treatment, whereas treatment with MK-7123, a CXCR2 antagonist, reduced neutrophil diapedesis in all conditions. In conclusion, our microengineered 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 hosts’ 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.  a1044-1549