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.

Public Health Relevance

There is no current therapy that reduces mortality in idiopathic pulmonary fibrosis (IPF). Alveolar macrophages, which are the initial defense-fighting cell in the lung, have a critical role in IPF development and progression. The studies in this application will define the molecular mechanisms that regulate alveolar macrophage phenotype and function and test a therapeutic target for preventing development and/or progression of the disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL114470-07
Application #
9752657
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Craig, Matt
Project Start
Project End
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Chanda, Diptiman; Otoupalova, Eva; Smith, Samuel R et al. (2018) Developmental pathways in the pathogenesis of lung fibrosis. Mol Aspects Med :
Qu, Jing; Zhu, Lanyan; Zhou, Zijing et al. (2018) Reversing Mechanoinductive DSP Expression by CRISPR/dCas9-mediated Epigenome Editing. Am J Respir Crit Care Med 198:599-609
Thannickal, Victor J; Antony, Veena B (2018) Is personalized medicine a realistic goal in idiopathic pulmonary fibrosis? Expert Rev Respir Med 12:441-443
Rangarajan, Sunad; Bone, Nathaniel B; Zmijewska, Anna A et al. (2018) Metformin reverses established lung fibrosis in a bleomycin model. Nat Med 24:1121-1127
Zhou, Yong; Horowitz, Jeffrey C; Naba, Alexandra et al. (2018) Extracellular matrix in lung development, homeostasis and disease. Matrix Biol 73:77-104
Cui, Huachun; Xie, Na; Banerjee, Sami et al. (2018) Impairment of Fatty Acid Oxidation in Alveolar Epithelial Cells Mediates Acute Lung Injury. Am J Respir Cell Mol Biol :
Hough, Kenneth P; Trevor, Jennifer L; Strenkowski, John G et al. (2018) Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol 18:54-64
Bernard, Karen; Logsdon, Naomi J; Benavides, Gloria A et al. (2018) Glutaminolysis is required for transforming growth factor-?1-induced myofibroblast differentiation and activation. J Biol Chem 293:1218-1228
Ge, Jing; Cui, Huachun; Xie, Na et al. (2018) Glutaminolysis Promotes Collagen Translation and Stability via ?-Ketoglutarate-mediated mTOR Activation and Proline Hydroxylation. Am J Respir Cell Mol Biol 58:378-390
Hough, Kenneth P; Wilson, Landon S; Trevor, Jennifer L et al. (2018) Unique Lipid Signatures of Extracellular Vesicles from the Airways of Asthmatics. Sci Rep 8:10340

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