# Biophysical Mechanisms of Hyperoxia-Induced Lung Injury

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2021 · $522,331

## Abstract

Acute lung injury and its more severe form, acute respiratory distress syndrome
(ARDS), are devastating illnesses with high rates of incidence and mortality. Patients
with acute lung injury are typically provided supplemental oxygen using positive
pressure mechanical ventilation, but this can lead to additional injury, termed ventilator-
induced lung injury (VILI). The long term objective of this proposal is to improve
understanding of the mechanisms by which the combination of exposure to high levels
of oxygen (hyperoxia) and overdistention (or stretch) of lung cells contributes to
ventilator-induced lung injury. The central hypothesis of this application is that
hyperoxia induces structural changes in alveolar epithelial and endothelial cells, as well
as macrophages, that alter their mechanical properties making them more susceptible
to injury caused by mechanical stretch. Mechanisms of the initiation of cell injury will be
investigated using primary cultures of mouse alveolar type II (AT2) epithelial cells,
primary human lung endothelial cells, mouse alveolar and bone marrow-derived
macrophages, cultures of mouse lung slices, and a mouse model of combined
hyperoxia and VILI. In Aim 1 we will test the hypothesis that exposure of cells or lung
slices causes changes in cell structural elements that increase the elastic modulus of
the cells through activation of RhoA. We will measure the Young’s modulus, an
indication of an object’s ability to deform, using atomic force microscopy in the
indentation mode, and we will determine how hyperoxia changes cytoskeletal structures
including f-actin, microtubules, and focal adhesions. In Aim 2 we will investigate how
hyperoxia increases stretch-induced cell detachment and injury. In Aim 3 we will test
the hypothesis that RhoA-mediated changes in structure and mechanical properties
increases lung injury in mice in a combined model of hyperoxia and VILI. The proposed
studies will investigate the biophysical mechanisms that contribute to lung injury during
mechanical ventilation and provide new insights into mechanotransduction, the process
of converting mechanical signals to biological signals.

## Key facts

- **NIH application ID:** 10145776
- **Project number:** 5R01HL151419-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** CHRISTOPHER M WATERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $522,331
- **Award type:** 5
- **Project period:** 2020-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145776

## Citation

> US National Institutes of Health, RePORTER application 10145776, Biophysical Mechanisms of Hyperoxia-Induced Lung Injury (5R01HL151419-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145776. Licensed CC0.

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