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Nat Biomed Eng. 2019 Jul;3(7):532-544. doi: 10.1038/s41551-019-0366-7. Epub 2019 Mar 11.

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

Author information

1
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA. okilic@alumni.stanford.edu.
2
Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. okilic@alumni.stanford.edu.
3
Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
4
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
5
Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA.
6
Institute for Translational Medicine and Science, Rutgers University, New Brunswick, NJ, USA.
7
Department of Medical Engineering, University of South Florida, Tampa, FL, USA.
8
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
9
Department of Neurologic Surgery, Mayo Clinic, Jacksonville, FL, USA.
10
Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. san@jhu.edu.
11
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. san@jhu.edu.
12
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA. san@jhu.edu.
13
Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea. san@jhu.edu.
14
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA. andre.levchenko@yale.edu.
15
Department of Biomedical Engineering, Yale University, New Haven, CT, USA. andre.levchenko@yale.edu.
16
Yale Systems Biology Institute, Yale University, West Haven, CT, USA. andre.levchenko@yale.edu.

Abstract

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.

PMID:
31150010
PMCID:
PMC6653686
[Available on 2019-09-11]
DOI:
10.1038/s41551-019-0366-7

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