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Modeling Ventilator-Induced Lung Injury and Neutrophil Infiltration to Infer Injury Interdependence

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Abstract

Acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI) are heterogeneous conditions. The spatiotemporal evolution of these heterogeneities is complex, and it is difficult to elucidate the mechanisms driving its progression. Through previous quantitative analyses, we explored the distributions of cellular injury and neutrophil infiltration in experimental VILI and discovered that VILI progression is characterized by both the formation of new injury in quasi-random locations and the expansion of existing injury clusters. Distributions of neutrophil infiltration do not correlate with cell injury progression and suggest a systemic response. To further examine the dynamics of VILI, we have developed a novel computational model that simulates damage (cellular injury progression and neutrophil infiltration) using a stochastic approach. Optimization of the model parameters to fit experimental data reveals that the range and strength of interdependence between existing and new damaged regions both increase as mechanical ventilation patterns become more injurious. The interdependence of cellular injury can be attributed to mechanical tethering forces, while the interdependence of neutrophils is likely due to longer-range cell signaling pathways.

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Acknowledgements

This work was supported by the National Institutes of Health Grants R01 HL151630 (“Predicting and Preventing Ventilator-Induced Lung Injury”; to B.J.S.) and F31 HL149268 (“Spatiotemporal evolution of lung injury during ventilator-induced lung injury”; to C.L.M.); and National Science Foundation Grant 2225554 (‘”RECODE: Defining Environmental Design Criteria for Directed Differentiation of Type 1 from Type 2 Lung Alveolar Epithelial Cells,” to B.J.S and C.L.M.). This work used the computing resources at the Center for Computational Mathematics, University of Colorado Denver, including the Alderaan cluster, supported by the National Science Foundation award OAC-2019089.

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Authors and Affiliations

  1. Department of Bioengineering, University of Colorado Denver | Anschutz Medical Campus, 12705 E. Montview Blvd., Suite 100, Aurora, CO, 80045, USA

    Courtney L. Mattson & Bradford J. Smith

  2. Pulmonary and Sleep Medicine, Department of Pediatrics, School of Medicine, University of Colorado, Aurora, CO, USA

    Bradford J. Smith

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  1. Courtney L. Mattson
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Mattson, C.L., Smith, B.J. Modeling Ventilator-Induced Lung Injury and Neutrophil Infiltration to Infer Injury Interdependence. Ann Biomed Eng 51, 2837–2852 (2023). https://doi.org/10.1007/s10439-023-03346-3

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