# Metabolic Regulation of Pro-Fibrotic Macrophages in Pulmonary Fibrosis

> **NIH NIH P01** · TULANE UNIVERSITY OF LOUISIANA · 2021 · $332,768

## Abstract

Idiopathic pulmonary fibrosis (IPF) is increasing in prevalence, and the recently approved anti-fibrotic
therapies have limited efficacy. Alveolar macrophages have a critical role lung injury and repair. Macrophages
in chronic disease typically exhibit apoptosis resistance, and their prolonged survival is generally associated
with disease progression due to polarization to a pro-fibrotic phenotype. The generation of mitochondrial ROS
(mtROS) in alveolar macrophages modulates pro-fibrotic polarization; however, the molecular mechanism(s)
regulating macrophage mtROS in fibrosis is not clearly defined. One of the NOX enzymes, NOX4, generates
mtROS with various stimuli and in several cell types, but the modulation of the macrophage phenotype has not
been linked to NOX4. Our preliminary data show that alveolar macrophages from IPF subjects express high
levels of the NOX4 gene compared to normal subjects, and there is more NOX4 localized in the mitochondria
of IPF alveolar macrophages. NOX1/4 inhibition with GKT137831 or silencing NOX4 significantly abrogates
mtROS. Moreover, GKT137831 down regulates pro-fibrotic polarization of macrophages and abrogates fatty
acid oxidation and oxidative phosphorylation, which is characteristic metabolism for pro-fibrotic macrophages.
In vivo, NOX4 modulates the polarization of alveolar macrophages to a pro-fibrotic phenotype. In addition,
NOX4-/- mice, which are protected from pulmonary fibrosis, have significantly less alveolar macrophages in the
BAL fluid suggesting either a defect in recruitment or an absence of apoptosis resistance. Our hypothesis is
that NOX4 modulates macrophage mtROS and metabolism to polarize alveolar macrophages to a pro-fibrotic
phenotype that is critical for fibrosis development. We will test this hypothesis with three specific aims. Aim 1
will determine if the Nox1/4 inhibitor (GKT137831) modulates alveolar macrophage metabolism and phenotype
in IPF subjects enrolled in a Phase IIb clinical trial. In Aim 2, we will determine the effects of NOX4 in
regulating mitochondrial metabolism and alveolar macrophage phenotype using pharmacologic (GKT137831)
and genetic approaches. Aim 3 will determine macrophage-specific roles of NOX4 in regulating fibrotic
responses to lung injury utilizing mice harboring a conditional deletion of NOX4 in macrophages. These studies
may delineate NOX4 as a critical regulator of metabolism and macrophage plasticity suggesting it is an ideal
therapeutic target to halt progression or reverse pulmonary fibrosis.

## Key facts

- **NIH application ID:** 10218253
- **Project number:** 5P01HL114470-10
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** A BRENT CARTER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $332,768
- **Award type:** 5
- **Project period:** 2013-09-16 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218253

## Citation

> US National Institutes of Health, RePORTER application 10218253, Metabolic Regulation of Pro-Fibrotic Macrophages in Pulmonary Fibrosis (5P01HL114470-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10218253. Licensed CC0.

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