# Netosis in Trauma mediated Acute Lung Injury

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2021 · $180,049

## Abstract

PROJECT SUMMARY
Up to 40% of critically injured trauma patients will develop a serious infectious complication during their inpatient
hospitalization and respiratory infections are the most common cause of sepsis in injured patients. While it is known
that traumatic injury triggers a sterile inflammatory response that can result in acute lung injury (ALI), the mechanism of
this and its contribution to the development of secondary infections such as pneumonia is not well understood. The
overarching goal of this research is to understand the role of the innate immune system in trauma induced lung injury in
order to provide new targets for treatment and prevention. We have recently established a mouse model of polytrauma
that recapitulates the increased susceptibility to gram negative pneumonia seen in critically injured patients. In
preliminary studies, we demonstrate that trauma alone induces both an acute lung injury and increased susceptibility to
Pseduomonas pneumonia. We further find an increase in neutrophil NETosis following a second insult with
pseudomonas bacteria. Neutrophil NETosis is a strong antimicrobial neutrophil response whereby activated neutrophils
extrude a web of DNA studded with cytotoxic granules which function to immobilize and kill invading pathogens. While
NETosis is a critical anti-infective pathway, excessive NETosis has been demonstrated to result in collateral damage to
host tissues. We also show that serum from traumatically injured mice can prime unactivated neutrophils for NETosis.
Based on these data we hypothesize that trauma primes neutrophils for NETosis causing ALI and an overexuberant
response to gram negative bacterial pneumonia after trauma. To test this hypothesis we propose two specific aims.
Aim 1: Determine if neutrophil NETosis triggered by polytrauma-induced ALI exacerbates pneumonia.
Aim 2: Define the the role of GCSF in promoting NETosis after polytrauma
AIM3: Define the contribution of neutrophil NETosis to the dysregulated immune response induced by a secondary
infection after trauma.
The knowledge gained from successfully achieving these aims will provide a novel pathway to prevent and treat ALI after
trauma and are clinically translatable as several current FDA approved therapeutics are known to have activity against
key enzymes required for NETosis and multiple specific therapeutics are currently being developed. This knowledge is
crucial so that Dr. Leonard’s laboratory can translate these to development of mechanistic therapies that may improve
patient outcomes.

## Key facts

- **NIH application ID:** 10371817
- **Project number:** 1K08GM137323-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jennifer Leonard
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $180,049
- **Award type:** 1
- **Project period:** 2021-09-14 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371817

## Citation

> US National Institutes of Health, RePORTER application 10371817, Netosis in Trauma mediated Acute Lung Injury (1K08GM137323-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10371817. Licensed CC0.

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