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Ventilator-Induced Lung Injury as a Dynamic Balance Between Epithelial Cell Damage and Recovery

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Abstract

Acute respiratory distress syndrome (ARDS) has a high mortality rate that is due in part to ventilator-induced lung injury (VILI). Nevertheless, the majority of patients eventually recover, which means that their innate reparative capacities eventually prevail. Since there are currently no medical therapies for ARDS, minimizing its mortality thus amounts to achieving an optimal balance between spontaneous tissue repair versus the generation of VILI. In order to understand this balance better, we developed a mathematical model of the onset and recovery of VILI that incorporates two hypotheses: (1) a novel multi-hit hypothesis of epithelial barrier failure, and (2) a previously articulated rich-get-richer hypothesis of the interaction between atelectrauma and volutrauma. Together, these concepts explain why VILI appears in a normal lung only after an initial latent period of injurious mechanical ventilation. In addition, they provide a mechanistic explanation for the observed synergy between atelectrauma and volutrauma. The model recapitulates the key features of previously published in vitro measurements of barrier function in an epithelial monolayer and in vivo measurements of lung function in mice subjected to injurious mechanical ventilation. This provides a framework for understanding the dynamic balance between factors responsible for the generation of and recovery from VILI.

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Acknowledgements

This work was supported by NIH Grant HL142702 and W81XWH-20-1-0696.

Funding

Funding was provided by Center for Scientific Review (Grant No. HL142702).

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Authors and Affiliations

  1. Department of Medicine, University of Vermont, Burlington, VT, 05405, USA

    Jason H. T. Bates

  2. Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, USA

    Gary F. Nieman & Michaela Kollisch-Singule

  3. Department of Biomedical Engineering, Tulane University, New Orleans, LA, USA

    Donald P. Gaver

  4. Department of Medicine, Larner College of Medicine, 149 Beaumont Avenue, Burlington, 05405-0075, USA

    Jason H. T. Bates

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  1. Jason H. T. Bates
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  4. Donald P. Gaver
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Contributions

Study concept and design: JHTB. Drafting of Manuscript: JHTB. Critical Revisions of Manuscript: DPG, MK-S, GFN. Statistical Analysis: JHTB. Obtaining Funding: GFN, DPG, JHTB.

Corresponding author

Correspondence to Jason H. T. Bates.

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Competing Interests

JHTB is a member of the advisory board and shareholder in Oscillavent, LLC. He is also a consultant for Respirator Sciences LLC and is co-applicant on patent Application WO2015127377 A1 (filed Feb 23, 2014) and International application no. PCT/US21/24537 (filed March 2, 2021). GFN has an Unconditional Education Grant from Drager Medical. GFN and MKS have lectured for Intensive Care On-line Network, Inc. (ICON). MKS has received an educational research grant from Dräger Medical Systems, Inc. The authors maintain that industry had no role in the design and conduct of the study; the collection, management, analysis, or interpretation of the data; nor the preparation, review, or approval of the manuscript.

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Associate Editor Chiara Bellini oversaw the review of this article.

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Bates, J.H.T., Nieman, G.F., Kollisch-Singule, M. et al. Ventilator-Induced Lung Injury as a Dynamic Balance Between Epithelial Cell Damage and Recovery. Ann Biomed Eng 51, 1052–1062 (2023). https://doi.org/10.1007/s10439-023-03186-1

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  • DOI: https://doi.org/10.1007/s10439-023-03186-1

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