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Effect of loading history on airway smooth muscle cell-matrix adhesions

Irons, Linda; Owen, Markus R.; O'Dea, Reuben D.; Brook, Bindi S.

Authors

Linda Irons linda.irons@nottingham.ac.uk

MARKUS OWEN markus.owen@nottingham.ac.uk
Professor of Mathematical Biology



Abstract

Integrin-mediated adhesions between airway smooth muscle (ASM) cells and the extracellular matrix (ECM) regulate how contractile forces generated within the cell are transmitted to its external environment. Environmental cues are known to influence the formation, size and survival of cell-matrix adhesions, but it is not yet known how they are affected by dynamic fluctuations associated with tidal breathing in the intact airway. Here we develop two closely-related theoretical models to study adhesion dynamics in response to oscillatory loading of the ECM, representing the dynamic environment of ASM cells in vivo. Using a discrete stochastic-elastic model, we simulate individual integrin binding and rupture events and observe two stable regimes in which either bond formation or bond rupture dominate, depending on the amplitude of the oscillatory loading. These regimes have either a high or low fraction of persistent adhesions, which could affect the level of strain transmission between contracted ASM cells and the airway tissue. For intermediate loading we observe a region of bistability and hysteresis due to shared loading between existing bonds; the level of adhesion depends on the loading history. These findings are replicated in a related continuum model, which we use to investigate the effect of perturbations mimicking deep inspirations (DIs). Due to the bistability, a DI applied to the high adhesion state could either induce a permanent switch to a lower adhesion state or allow a return of the system to the high adhesion state. Transitions between states are further influenced by the frequency of oscillations, cytoskeletal or ECM stiffnesses and binding affinities, which modify the magnitudes of the stable adhesion states as well as the region of bistability. These findings could explain (in part) the transient bronchodilatory effect of a DI observed in asthmatics compared to a more sustained effect in normal subjects.

Journal Article Type Article
Publication Date Jun 5, 2018
Journal Biophysical Journal
Print ISSN 0006-3495
Electronic ISSN 0006-3495
Publisher Biophysical Society
Peer Reviewed Peer Reviewed
Volume 114
Issue 11
Pages 2679-2690
APA6 Citation Irons, L., Owen, M. R., O'Dea, R. D., & Brook, B. S. (2018). Effect of loading history on airway smooth muscle cell-matrix adhesions. Biophysical Journal, 114(11), (2679-2690). doi:10.1016/j.bpj.2018.04.026. ISSN 0006-3495
DOI https://doi.org/10.1016/j.bpj.2018.04.026
Publisher URL https://www.sciencedirect.com/science/article/pii/S0006349518305204?via%3Dihub
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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