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.
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Thrombin induces IL-8/CXCL8 expression by DCLK1-dependent RhoA and YAP activation in human lung epithelial cells
Journal of Biomedical Science Open Access 11 November 2022
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The authors declare that all data supporting the findings of this study are available within the paper and its Supplementary Information. The source data for the figures in this study are available in figshare (https://doi.org/10.6084/m9.figshare.7639898)83.
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This work was supported by National Institutes of Health grants U01 CA155758 (A.L), U54 CA209992 (A.L), R01 HL107361 (S.S.A) and P01 HL114471 (R.A.P., S.B.L. and S.S.A.). O.K. was a recipient of the American Heart Association Postdoctoral Fellowship (grant no. 13POST17140090). This work was also supported by a grant from the American Asthma Foundation (A.L. and S.S.A). S.S.A. was also supported by a Discovery Award and a Catalyst Award from the Johns Hopkins University.
O.K, S.S.A. and A.L. have a pending patent (US Patent Application 15/739,639) related to the work in this manuscript. The remaining authors declare no competing interests.
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Tidal breathing in bronchial-chip
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Kilic, O., Yoon, A., Shah, S.R. et al. A microphysiological model of the bronchial airways reveals the interplay of mechanical and biochemical signals in bronchospasm. Nat Biomed Eng 3, 532–544 (2019). https://doi.org/10.1038/s41551-019-0366-7
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