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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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Electric Cell-Substrate Impedance Sensing (ECIS) as a Platform for Evaluating Barrier-Function Susceptibility and Damage from Pulmonary Atelectrauma
Biophysical insults that either reduce barrier function (COVID-19, smoke inhalation, aspiration, and inflammation) or increase mechanical stress (surfactant dysfunction) make the lung more susceptible to atelectrauma. We investigate the susceptibility and time-dependent disruption of barrier function associated with pulmonary atelectrauma of epithelial cells that occurs in acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). This in vitro study was performed using Electric Cell-substrate Impedance Sensing (ECIS) as a noninvasive evaluating technique for repetitive stress stimulus/response on monolayers of the human lung epithelial cell line NCI-H441. Atelectrauma was mimicked through recruitment/derecruitment (RD) of a semi-infinite air bubble to the fluid-occluded micro-channel. We show that a confluent monolayer with a high level of barrier function is nearly impervious to atelectrauma for hundreds of RD events. Nevertheless, barrier function is eventually diminished, and after a critical number of RD insults, the monolayer disintegrates exponentially. Confluent layers with lower initial barrier function are less resilient. These results indicate that the first line of defense from atelectrauma resides with intercellular binding. After disruption, the epithelial layer community protection is diminished and atelectrauma ensues. ECIS may provide a platform for identifying damaging stimuli, ventilation scenarios, or pharmaceuticals that can reduce susceptibility or enhance barrier-function recovery.
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- Award ID(s):
- 1706801
- PAR ID:
- 10472627
- Publisher / Repository:
- MDPI
- Date Published:
- Journal Name:
- Biosensors
- Volume:
- 12
- Issue:
- 6
- ISSN:
- 2079-6374
- Page Range / eLocation ID:
- 390
- Subject(s) / Keyword(s):
- ECIS technology ARDS VILI atelectrauma barrier function pulmonary disease lung mechanical ventilation
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/bios12060390
