# Dissecting the molecular mechanisms of lung injury during mechanical ventilation

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $548,938

## Abstract

Project Summary
The acute respiratory distress syndrome (ARDS) is a deadly condition characterized by the rapid onset of
hypoxemia and respiratory failure. The mainstay of therapy for ARDS patients is supportive care with
mechanical ventilation (MV). Although life-saving, mechanical ventilation can exacerbate lung injury and even
cause de novo injury, known as ventilator induced lung injury (VILI). VILI arises from mechanical forces during
MV including excessive stretch (volutrauma), excessive pressure (barotrauma), and injury due to repeated
collapse and reopening of lung units (atelectrauma). The molecular mechanisms by which these mechanical
forces exacerbate lung injury remain poorly understood. Clinicians try to prevent VILI by monitoring airway
pressures and using low tidal volumes, but injury persists even when these parameters are in a “safe” range.
Currently, there are no pharmacologic therapies to prevent or treat VILI in patients with ARDS. mTORC1 is a
central regulator of cell growth and lipid metabolism. In contrast to canonical activation of mTORC1 under
favorable growth conditions, we recently discovered that mTORC1 is activated in lung epithelial cells following
injurious mechanical ventilation. We also found that pharmacologic mTORC1 inhibition prevents lung injury
during mechanical ventilation. We hypothesize that mTORC1 activation plays a central role in mediating VILI
and represents a novel therapeutic target in ARDS. We will determine the mechanisms by which mTORC1
inhibition prevents VILI using mice with mTORC1 inactivation in type I and type II alveolar epithelial cells as
well as novel in vitro models of mechanical ventilation in the human lung. In Aim 1 we will identify how
mTORC1 activation induces surfactant dysfunction during ventilator induced lung injury. In Aim 2 we will
identify the mechanisms by which mTORC1 regulates epithelial membrane repair following injurious
mechanical ventilation. In Aim 3 we will use clinically relevant 2-hit models that utilize mechanical ventilation
following lung injury from sepsis or influenza pneumonia to test the efficacy of mTORC1 inhibition to prevent
VILI in ARDS. Our studies will provide an in-depth understanding of how mTORC1 activation impairs surfactant
function and membrane repair during VILI and will identify novel drug targets for patients with ARDS.

## Key facts

- **NIH application ID:** 10352404
- **Project number:** 5R01HL142767-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Joshua A Englert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $548,938
- **Award type:** 5
- **Project period:** 2021-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10352404

## Citation

> US National Institutes of Health, RePORTER application 10352404, Dissecting the molecular mechanisms of lung injury during mechanical ventilation (5R01HL142767-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10352404. Licensed CC0.

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