# Lung Macrophage Metabolic Reprogramming in Asbestos-Induced Toxicity

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $333,208

## Abstract

Asbestos-induced toxicity remains to be a significant environmental condition. Despite strict regulatory
controls to limit exposure, more than 1.3 million workers are exposed to hazardous levels of asbestos every
year, which results in more than 100,000 deaths annually in the United States. One critical factor that
contributes to the severity of toxicity in asbestos exposure is the generation of mitochondrial ROS (mtROS),
which modulates alternative activation of lung macrophages; however, the molecular mechanism(s) regulating
macrophage mtROS generation is not clearly defined. One of the NOX enzymes, NOX4, induces mtROS with
various stimuli and in several cell types, but the modulation of the macrophage phenotype is not known to be
mediated by NOX4. Our preliminary data show that lung macrophages from asbestos-injured subjects express
high levels of the NOX4 gene compared to normal subjects. Inhibition or silencing NOX4 significantly
abrogates mtROS. More importantly, the NOX1/4 inhibitor (GKT137831) abolishes alternative activation of
macrophages. One important characteristic of alternatively activated macrophages is metabolic reprogramming
from glycolytic metabolism to fatty acid oxidation, which is necessary to support long-term cellular activities.
NOX1/4 inhibition attenuates asbestos-induced fatty acid oxidation. Similar observations were recapitulated in
NOX4-/- mice. Lung macrophages from NOX4-/- mice displayed classical activation unlike the wild type mice,
which had pro-fibrotic activation of macrophages. Furthermore, NOX4-/- mice were protected from asbestos-
induced toxicity. Our hypothesis is that NOX4-mediated mtROS modulates metabolic reprogramming,
alternative activation, and apoptosis resistance of lung macrophages, which promotes asbestos-induced
toxicity. We will test this hypothesis with three specific aims. In Aim 1, the role of macrophage NOX4 in
macrophage plasticity and in the pathogenesis of asbestos-induced toxicity will be tested in mice harboring a
deletion of NOX4 in macrophages. Aim 2 will test the role of NOX4-derived mtROS in metabolic
reprogramming and phenotypic plasticity using genetic approaches in asbestos-exposed macrophages. Aim 3
will test the role of NOX4 on the metabolism and phenotype of lung macrophages from asbestos-injured
subjects ex vivo with GKT137831 and RNAi-mediated NOX4 silencing. These studies may uncover NOX4 as
an ideal therapeutic target to attenuate asbestos-induced toxicity by modulating mitochondrial metabolism and
macrophage plasticity.

## Key facts

- **NIH application ID:** 9889125
- **Project number:** 5R01ES015981-13
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** A BRENT CARTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $333,208
- **Award type:** 5
- **Project period:** 2007-09-10 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889125

## Citation

> US National Institutes of Health, RePORTER application 9889125, Lung Macrophage Metabolic Reprogramming in Asbestos-Induced Toxicity (5R01ES015981-13). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9889125. Licensed CC0.

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