A microphysiological model of the bronchial airways reveals the interplay of mechanical and biochemical signals in bronchospasm

• Published in: Nature biomedical engineering Vol. 3; no. 7; pp. 532 - 544
• Main Authors: Kilic, Onur, Yoon, Arum, Shah, Sagar R., Yong, Hwan Mee, Ruiz-Valls, Alejandro, Chang, Hao, Panettieri, Reynold A., Liggett, Stephen B., Quiñones-Hinojosa, Alfredo, An, Steven S., Levchenko, Andre
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2019; Nature Publishing Group
• Subjects: 13/106; 13/62; 631/1647/277; 639/166/985; 692/308/1426; 692/699/1785/31; Air flow; Asthma; Biochemical Phenomena - genetics; Biochemistry; Biomechanical Phenomena - genetics; Biomechanical Phenomena - physiology; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Bronchi - physiology; Bronchial Spasm - genetics; Bronchial Spasm - pathology; Bronchospasm; Cell Communication - physiology; Compressive properties; Contraction; Couplings; Epithelial cells; Epithelial Cells - physiology; Feedback; Feedback loops; Gene expression; Gene Expression Regulation; Humans; Isoenzymes - metabolism; Lab-On-A-Chip Devices; Mathematical models; Mechanotransduction, Cellular - genetics; Mimicry; Molecular modelling; Muscle contraction; Muscle Contraction - physiology; Muscle, Smooth - physiology; Muscles; Pathogenesis; Positive feedback; Prostaglandin endoperoxide synthase; Prostaglandin-Endoperoxide Synthases - genetics; Prostaglandin-Endoperoxide Synthases - metabolism; Respiratory tract; Scale models; Smooth muscle; Stress, Mechanical; Stress, Physiological; Transcription; Yes-associated protein
• ISSN: 2157-846X; 2157-846X
• DOI: 10.1038/s41551-019-0366-7

In asthma, the contraction of the airway smooth muscle and the subsequent decrease in airflow involve a poorly understood set of mechanical and biochemical events. Organ-level and molecular-scale models of the airway are frequently based on purely mechanical or biochemical considerations and do not account for physiological mechanochemical couplings. Here, we present a microphysiological model of the airway that allows for the quantitative analysis of the interactions between mechanical and biochemical signals triggered by compressive stress on epithelial cells. We show that a mechanical stimulus mimicking a bronchospastic challenge triggers the marked contraction and delayed relaxation of airway smooth muscle, and that this is mediated by the discordant expression of cyclooxygenase genes in epithelial cells and regulated by the mechanosensor and transcriptional co-activator Yes-associated protein. A mathematical model of the intercellular feedback interactions recapitulates aspects of obstructive disease of the airways, which include pathognomonic features of severe difficult-to-treat asthma. The microphysiological model could be used to investigate the mechanisms of asthma pathogenesis and to develop therapeutic strategies that disrupt the positive feedback loop that leads to persistent airway constriction.
A microphysiological model of the bronchial airways enables the study of the mechanochemical feedback interactions between smooth muscle cells and epithelial cells that underlie bronchospasm.