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

Nature Biomedical Engineering volume 3, pages 532–544 (2019)Cite this article

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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.

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Fig. 1: Bronchial-chip results indicate positive feedback between smooth-muscle contraction and compressive stress on epithelium.
Fig. 2: Longer-term intercellular interaction through eicosanoid production.
Fig. 3: Eicosanoid production is regulated by the modulation of cyclooxygenase isozymes by compressive stress.
Fig. 4: Compressive stress is relayed to cyclooxygenase through the mechanosensor YAP.
Fig. 5: Positive and negative feedback between NHBE and HASM.
Fig. 6: Mechanochemical feedback interactions can underlie distinct modes of bronchospasm.

Data availability

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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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA

    Onur Kilic, Sagar R. Shah, Hao Chang & Andre Levchenko

  2. Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Onur Kilic, Arum Yoon, Hwan Mee Yong & Steven S. An

  3. Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Alejandro Ruiz-Valls

  4. Institute for Translational Medicine and Science, Rutgers University, New Brunswick, NJ, USA

    Reynold A. Panettieri Jr

  5. Department of Medical Engineering, University of South Florida, Tampa, FL, USA

    Stephen B. Liggett

  6. Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    Stephen B. Liggett

  7. Department of Neurologic Surgery, Mayo Clinic, Jacksonville, FL, USA

    Alfredo Quiñones-Hinojosa

  8. Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Steven S. An

  9. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA

    Steven S. An

  10. Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea

    Steven S. An

  11. Department of Biomedical Engineering, Yale University, New Haven, CT, USA

    Andre Levchenko

  12. Yale Systems Biology Institute, Yale University, West Haven, CT, USA

    Andre Levchenko

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Contributions

O.K., S.S.A. and A.L. conceptualized the work. O.K. carried out the device and platform design and fabrication. O.K., H.M.Y., A.Y., S.R.S., A.R.-V. and H.C. carried out the experiments. O.K. and A.L. performed the theoretical modelling. All authors contributed to data analysis, discussion and interpretation. O.K., S.S.A. and A.L. wrote and revised the manuscript with input from all authors.

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Correspondence to Onur Kilic, Steven S. An or Andre Levchenko.

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Competing interests

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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Supplementary information

Supplementary Information

Supplementary figures, tables and legend for Supplementary Video 1.

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Supplementary Video 1

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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