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.

Public Health Relevance

There is no current therapy that reduces mortality in asbestos-induced toxicity. Lung macrophages, which are the initial defense-fighting cell in the lung, have a critical role in asbestos-induced toxicity. The studies in this application will define the molecular mechanism(s) that regulate metabolism and function of lung macrophages and may identify a therapeutic target for preventing toxicity from asbestos exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES015981-11A1
Application #
9522373
Study Section
Systemic Injury by Environmental Exposure (SIEE)
Program Officer
Carlin, Danielle J
Project Start
2007-09-10
Project End
2023-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
11
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Bernard, Karen; Logsdon, Naomi J; Miguel, Veronica et al. (2017) NADPH Oxidase 4 (Nox4) Suppresses Mitochondrial Biogenesis and Bioenergetics in Lung Fibroblasts via a Nuclear Factor Erythroid-derived 2-like 2 (Nrf2)-dependent Pathway. J Biol Chem 292:3029-3038
Gu, Linlin; Larson-Casey, Jennifer L; Carter, A Brent (2017) Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization. FASEB J 31:3072-3083
Jiang, Chunsun; Liu, Gang; Luckhardt, Tracy et al. (2017) Serpine 1 induces alveolar type II cell senescence through activating p53-p21-Rb pathway in fibrotic lung disease. Aging Cell 16:1114-1124
Winters, Christopher J; Koval, Olha; Murthy, Shubha et al. (2016) CaMKII inhibition in type II pneumocytes protects from bleomycin-induced pulmonary fibrosis by preventing Ca2+-dependent apoptosis. Am J Physiol Lung Cell Mol Physiol 310:L86-94
Larson-Casey, Jennifer L; Deshane, Jessy S; Ryan, Alan J et al. (2016) Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis. Immunity 44:582-596
Larson-Casey, Jennifer L; Carter, A Brent (2016) Determination of H2O2 Generation by pHPA Assay. Bio Protoc 6:
Larson-Casey, Jennifer L; Carter, A Brent (2016) Assay to evaluate BAL Fluid regulation of Fibroblast ?-SMA Expression. Bio Protoc 6:
He, Chao; Larson-Casey, Jennifer L; Gu, Linlin et al. (2016) Cu,Zn-Superoxide Dismutase-Mediated Redox Regulation of Jumonji Domain Containing 3 Modulates Macrophage Polarization and Pulmonary Fibrosis. Am J Respir Cell Mol Biol 55:58-71
Murthy, Shubha; Larson-Casey, Jennifer L; Ryan, Alan J et al. (2015) Alternative activation of macrophages and pulmonary fibrosis are modulated by scavenger receptor, macrophage receptor with collagenous structure. FASEB J 29:3527-36
Surolia, Ranu; Karki, Suman; Kim, Hyunki et al. (2015) Heme oxygenase-1-mediated autophagy protects against pulmonary endothelial cell death and development of emphysema in cadmium-treated mice. Am J Physiol Lung Cell Mol Physiol 309:L280-92

Showing the most recent 10 out of 27 publications