# Preserving Epithelial Barrier Integrity in Ventilator-Induced Lung Injury

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2024 · $715,908

## Abstract

PROJECT SUMMARY
Up to 40% of ARDS patients lose their battle with acute respiratory distress syndrome (ARDS). Many
of these patients succumb because ongoing ventilator-induced lung injury (VILI) overwhelms the innate
capacity of the lung to repair itself. On the other hand, many ARDS patients go on to recover, which
means that their reparative capacities eventually prevail. Since there are currently no medical therapies
for ARDS, minimizing its mortality amounts to achieving an optimal balance between spontaneous
tissue repair versus the generation of VILI. However, one-size-fits-all strategies for managing ARDS
have had limited success in reducing mortality, and the heterogeneity of ARDS is such that empirical
searches are very unlikely to lead to optimal ventilation strategies. Progress must thus be based on a
fundamental understanding of VILI mechanisms, so understanding the balance between injury and
repair in VILI remains a pressing unmet medical need. We have shown in vivo that the timing of the
ventilatory cycle is critically important to the prevention of cyclic airway recruitment and derecruitment
(RD) that leads to VILI. Furthermore, we have shown in vitro that, following onset of RD, the physical
integrity of an epithelial monolayer remains normal for a period of time before decreasing quasi-
exponentially, which is reminiscent of cancer survival curves governed by multi-hit mechanisms.
Accordingly, our overarching hypothesis is that the progression of VILI involves a multi-hit
mechanism leading to dysfunction of the blood-gas barrier, and that eventual recovery from
VILI is determined by whether the mechanical ventilation regimen being applied allows barrier
dysfunction to be counteracted by barrier healing. The overall goal of our research is to determine
in detail how both the progression and resolution of VILI are influenced by the current status of lung
injury and by the relative contributions of RD versus tissue over-distension and identify modes of
ventilation that can adapt successfully to a patient's own pathophysiology. Analysis of experimental
findings will be incorporated into a computational model to develop biopredictors that can forecast
whether injury or recovery will prevail in a given situation based on physiologic measurements at the
bedside. We will achieve this goal by measuring how barrier function in epithelial cell monolayers either
degrades or improves following application of controlled levels of atelectrauma, and by determining
how lung injury in pig models of ARDS either further develops or resolves with different mechanical
ventilation strategies that vary in their degrees of injuriousness. Computational modeling informed by
the experiment results will be used to explore energy dissipation within the respiratory cycle as a
biopredictor of patient outcome. By taking this approach, we expect to advance the design of optimal
ventilation strategies for ARDS that are adaptive and personalized to a given patient.

## Key facts

- **NIH application ID:** 10881292
- **Project number:** 2R01HL142702-05A1
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Jason HT Bates
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $715,908
- **Award type:** 2
- **Project period:** 2018-09-10 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881292

## Citation

> US National Institutes of Health, RePORTER application 10881292, Preserving Epithelial Barrier Integrity in Ventilator-Induced Lung Injury (2R01HL142702-05A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10881292. Licensed CC0.

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