# Preserving Epithelial Barrier Integrity in Ventilator-Induced Lung Injury

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $633,038

## Abstract

PROJECT SUMMARY
The distressingly high mortality from acute respiratory distress syndrome (ARDS) represents a dramatic loss of
quality human life-years. No medicines have yet been developed that treat ARDS, so management remains
purely supportive as patients are nursed through their illness in a critical care setting. A key component of this
management involves mechanical ventilation. Unfortunately, the stresses and strains of mechanical ventilation
can further damage already injured lung tissues, causing lung compliance to decrease and the stresses and
strains of mechanical ventilation to increase commensurately. This, in turn, worsens tissue damage in a vicious
cycle that is often ultimately fatal. Accordingly, the central premise of this proposal is that managing ARDS
requires, above all else, the minimization of VILI. Our prior studies lead to the over-arching hypothesis that the
development of ARDS occurs only once repetitive recruitment and derecruitment (RecDer) of lung units
initiates an epithelial leak that allows fluid and proteins to begin to accumulate in the airspaces. The
consequences of allowing this process to start are dire; surfactant function becomes impaired, surface tension
and tissue stresses increase, and the leak worsens in a vicious cycle that accelerates indefinitely. Once
underway, this process is difficult to reverse and is exacerbated by over-distension (OD) of the lung tissues,
making its avoidance paramount for patients at risk of developing ARDS. Our goal is to comprehensively test
this hypothesis both in vitro and in vivo in a range of three relevant model systems: 1) using biofluid mechanics
studies we will investigate fundamental interactions that may lead to RecDer, and at the cellular level in vitro
we will determine how both OD of lung tissue and repetitive RecDer of lung airspaces act individually and
synergistically to damage the airway epithelium in epithelial cell monolayers grown on the inside of compliant
tubes subjected to stretch and/or liquid bubble passage, respectively, 2) at the whole lung level in vivo we will
determine how over-distension and RecDer lead to leak of proteinaceous fluid into the lung airspaces and
cause derangements in lung mechanics and 3) we will determine how VILI can be minimized in a clinically
relevant porcine surfactant deactivation model of heterogeneous ARDS subjected to a variety of modes of
mechanical ventilation that apply differing relative degrees of tissue over-distention and RecDer. The data
collected in Aims 1 and 2 will inform the development of a computational model that predicts how VILI
develops over time as a result of the epithelial damage caused by RecDer and the exacerbating influences of
overdistension. The model will be tested under clinically relevant conditions in Aim 3. These studies will
establish the pathophysiologic understanding upon which personalized approaches to mechanical ventilation
that minimize VILI can be developed for individual ARDS pat...

## Key facts

- **NIH application ID:** 9964893
- **Project number:** 5R01HL142702-03
- **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:** 2020
- **Award amount:** $633,038
- **Award type:** 5
- **Project period:** 2018-09-10 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964893

## Citation

> US National Institutes of Health, RePORTER application 9964893, Preserving Epithelial Barrier Integrity in Ventilator-Induced Lung Injury (5R01HL142702-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9964893. Licensed CC0.

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