Breathing on Chip: Biomechanical forces change airway epithelial cell biology in a human Airway Lung‐Chip

Human lung function is intricately linked to the mechanics of breathing; however, it remains unknown whether and how these mechanical cues shape human lung cellular biology. While respiration-related strains and fluid flows have been suggested to promote alveolar epithelial cell function, the study of such fundamental mechanisms in the conducting airway epithelium has been hindered by the lack of suitable in vitro airway models. Here, we developed a model of human bronchial airway epithelium using well-differentiated primary cell cultures on a commercial Organs-on-Chips platform that enables the application of breathing-associated airflow and cyclic strain. It furthermore features optional endothelial cell co-culture to allow for crosstalk with the vascular compartment. Using this model, we evaluated the impact of airflow and physiological levels of cyclic strain on airway epithelial cell differentiation and function. Our findings suggest that breathing-associated mechanical stimulation changes epithelial composition, reduces secretion of IL-8, and downregulates gene expression of matrix metalloproteinase 9, fibronectin, and other extracellular matrix (ECM) factors. These results indicate that breathing-associated forces are important modulators of airway epithelial cell biology and that their fine-tuned application could generate models of specific epithelial phenotypes and pathologies.