Here we describe development of a human ‘lung small airway-on-a-chip’ containing a differentiated, mucociliary, bronchiolar epithelium and an underlying microvascular endothelium that experiences fluid flow, which enables analysis of organ-level lung pathophysiology in vitro. Exposure of the epithelium to IL-13 reconstitutes the goblet cell hyperplasia, cytokine hypersecretion and decreased ciliary function of asthmatics. Small airway chips lined by epithelial cells from chronic obstructive pulmonary disease patients recapitulate features of the disease including selective cytokine hypersecretion, increased neutrophil recruitment, and clinical exacerbations by exposure to viral and bacterial infections. Using this robust in vitro method for modeling human lung inflammatory disorders, it is possible to detect synergistic effects of lung endothelium and epithelium on cytokine secretion, identify new biomarkers of disease exacerbation, and measure therapeutic responses to anti-inflammatory compounds that inhibit cytokine-induced recruitment of circulating neutrophils under flow.
