# Targeting glutamine metabolism during the development and resolution of acute lung injury

> **NIH NIH K08** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $134,754

## Abstract

PROJECT SUMMARY/ABSTRACT
Acute respiratory distress syndrome (ARDS) is a devastating lung disease in which excessive inflammation leads
to lung dysfunction and often death. Attempts to use anti-inflammatory medications have been unsuccessful.
Due to their high metabolic demands, neutrophils, macrophages, and lymphocytes rely upon glutamine
metabolism for activation and function. Glutamine metabolism may thus represent a novel target to modulate the
excessive, dysregulated inflammation seen in ARDS. In this proposal, the role of glutamine in established acute
lung injury (ALI) will be explored via use of a glutamine analogue, DON (6-diazo-5-oxo-l-norleucine), which binds
to and inhibits glutamine-utilizing enzymes and transporters. This inhibitor will be studied in two in vivo models
of ARDS: intratracheal (IT) lipopolysaccharide (LPS) and IT bleomycin. These models allow evaluation of both
the inflammatory phase, when neutrophils and inflammatory macrophages are the predominant cell types, and
the resolution phase, when lymphocytes and macrophages mediate lung repair. Additionally, these models will
allow us to study lung injury that resolves over time (LPS) and injury that progresses to fibrosis (bleomycin). Our
initial studies suggest that DON ameliorates inflammation and promotes recovery in both models. Our hypothesis
is that glutamine modulates immune responses, and by targeting glutamine metabolism the unremitting,
dysregulated inflammation and wound healing in ALI can be mitigated. Aim 1 tests the hypothesis that inhibition
of glutamine metabolism reduces lung inflammation and promotes resolution of injury. Following induction of ALI
with bleomycin, mice will receive DON either during established inflammation or later during the development of
fibrosis. The effects of these inhibitors on inflammation and resolution of lung injury with be assessed. Aim 2
tests the hypothesis that DON modulates neutrophil, macrophage, and lymphocyte activity and metabolism in
vitro. Aim 3 tests the hypothesis that DON modulates the lung metabolome and assesses changes in gene
expression within lung inflammatory cells. Changes in metabolic pathways will be assessed by measurement of
metabolites within the lungs. These experiments will provide greater understanding of the role of glutamine
metabolism in ALI, both in individual immune cells and as an integrated process within the lungs, and will explore
a novel mechanism by which to modulate pulmonary inflammation. Additionally, this proposal will facilitate
development of essential skills and enhanced understanding of immunology and metabolism that will allow the
candidate to become an academic physician-scientist. The candidate and her mentor have designed a training
plan that combines this research proposal with coursework in immunology, metabolism, bioethics, statistics, and
grantsmanship to build the foundation necessary for successful career development. They have also assembled
an advisory committee cons...

## Key facts

- **NIH application ID:** 10411900
- **Project number:** 5K08HL148529-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Christine Lee Vigeland
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $134,754
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10411900

## Citation

> US National Institutes of Health, RePORTER application 10411900, Targeting glutamine metabolism during the development and resolution of acute lung injury (5K08HL148529-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10411900. Licensed CC0.

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