# The Role of Mitochondrial Metabolism in Neutrophilic Lung Inflammation

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $692,450

## Abstract

SUMMARY
 The fundamental role of neutrophils in host defense against pathogens is well established from animal
models of infection and the increased susceptibility to infection in neutropenic patients. Despite this, many
aspects of neutrophil biology remain underexplored. The metabolic programs needed to support antimicrobial
neutrophil functions are poorly understood and the degree of plasticity these cells may achieve in disease
states is not known. We have leveraged unique approaches to identify a novel association between increased
infection risk in patients and a polymorphism in Cpt1a. Carnitine palmitoyltransferase 1a (Cpt1a) is required for
mitochondrial metabolism of long chain fatty acids. Using a pharmacologic inhibitor of CPT1a and multiple
murine models of bacterial pneumonia, we have demonstrated that CPT1a inhibition increased susceptibility to
infection by decreasing neutrophil mobilization to, and activation at, the site of infection. We provide additional
preliminary data to support a model whereby neutrophil mitochondria metabolize fatty acids to generate ATP,
which is necessary for amplification of activating signals required for neutrophil activation, chemotaxis, and
antibacterial functions. Based on these findings, we will test the overall hypothesis that fatty acid metabolism is
an essential metabolic program for neutrophil trafficking and antibacterial defense in the lung. Specifically, we
will test the sub-hypotheses that (i) fatty acid metabolism is an important mechanism for mitochondrial ATP
production in neutrophils, (ii) fatty acid-derived mitochondrial ATP is required for amplification of neutrophil
activating signals, and (iii) disruption of fatty acid metabolism impairs neutrophil activation, chemotaxis,
antibacterial defenses, and neutrophilic lung inflammation. Specific Aim 1 will define the role of fatty acid
metabolism on neutrophil energetics, migration, and effector functions. This work will establish the contribution
of fatty acid metabolism to mitochondrial ATP production in neutrophils, define the role of fatty acid metabolism
in neutrophil activation, and determine the importance of fatty acid metabolism for neutrophil antibacterial
functions. Specific Aim 2 will determine the effect of inactivation of fatty acid metabolism on neutrophilic lung
inflammation. This work will use multiple single-cell approaches to define neutrophil plasticity and activation
heterogeneity in the infected lung microenvironment. Further, this Aim will determine the effects of fatty acid
metabolism inhibition on neutrophilic lung inflammation. Completion of these Aims will establish fatty acid
oxidation as an essential metabolic program to support antimicrobial neutrophil functions and add to the
current prevailing paradigm that neutrophils rely solely on aerobic glycolysis as a metabolic program. Further,
these studies will determine the functional consequences of neutrophil heterogeneity at the site of infection and
establish ...

## Key facts

- **NIH application ID:** 9945265
- **Project number:** 1R01HL152210-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Michael James Noto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $692,450
- **Award type:** 1
- **Project period:** 2020-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9945265

## Citation

> US National Institutes of Health, RePORTER application 9945265, The Role of Mitochondrial Metabolism in Neutrophilic Lung Inflammation (1R01HL152210-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9945265. Licensed CC0.

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