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Modeling the Progression of Epithelial Leak Caused by Overdistension

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Abstract

Mechanical ventilation is necessary for treatment of the acute respiratory distress syndrome but leads to overdistension of the open regions of the lung and produces further damage. Although we know that the excessive stresses and strains disrupt the alveolar epithelium, we know little about the relationship between epithelial strain and epithelial leak. We have developed a computational model of an epithelial monolayer to simulate leak progression due to overdistension and to explain previous experimental findings in mice with ventilator-induced lung injury. We found a nonlinear threshold-type relationship between leak area and increasing stretch force. After the force required to initiate the leak was reached, the leak area increased at a constant rate with further increases in force. Furthermore, this rate was slower than the rate of increase in force, especially at end-expiration. Parameter manipulation changed only the leak-initiating force; leak area growth followed the same trend once this force was surpassed. These results suggest that there is a particular force (analogous to ventilation tidal volume) that must not be exceeded to avoid damage and that changing cell physical properties adjusts this threshold. This is relevant for the development of new ventilator strategies that avoid inducing further injury to the lung.

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Acknowledgments

This study was supported by National Institutes of Health grants R01 HL-124052 and P20 GM-103532.

Conflicts of Interest

Katharine L. Hamlington, Baoshun Ma, Bradford J. Smith, and Jason H. T. Bates declare that they have no conflicts of interest.

Ethical Standards

No human studies were carried out by the authors for this article. No animal studies were carried out by the authors for this article.

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Authors and Affiliations

  1. Department of Medicine, Vermont Lung Center, University of Vermont College of Medicine, 149 Beaumont Avenue, HSF 228, Burlington, VT, 05405-0075, USA

    Katharine L. Hamlington, Baoshun Ma, Bradford J. Smith & Jason H. T. Bates

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  1. Katharine L. Hamlington
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  2. Baoshun Ma
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  3. Bradford J. Smith
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Correspondence to Jason H. T. Bates.

Additional information

Associate Editor Aleksander S. Popel oversaw the review of this article.

Electronic Supplementary Material

Below is the link to the electronic supplementary material. The movie shows the leak progression in the 45-cell network. Stretch force F s = 0.07, spring stiffness distribution k = 1, force threshold F t = 0.2, and cell edge length h = 1. The shading represents the value of the maximum spring force within each cell.

Supplementary material 1 (MOV 6518 kb)

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Hamlington, K.L., Ma, B., Smith, B.J. et al. Modeling the Progression of Epithelial Leak Caused by Overdistension. Cel. Mol. Bioeng. 9, 151–161 (2016). https://doi.org/10.1007/s12195-015-0426-3

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  • DOI: https://doi.org/10.1007/s12195-015-0426-3

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