There is a strong association between fibrotic lung disease and oxidative stress. Recent studies from our laboratory implicate the reactive oxygen species-generating enzyme, NADPH oxidase-4 (N0X4) in lung fibrosis. N0X4 mediates myofibroblast differentiation, matrix synthesis, and contractility;siRNA targeting of NOX4 abrogates fibrosis in animal models of non-infectious lung injury. Other reported studies of systemic N0X4 deficiency in mice further support the concept that N0X4 is critical for in-vivo fibrogenesis;however, the mechanisms and potential cell-specific effects of N0X4 remain unclear. N0X4 is expressed in fibrotic regions of alveolar and vascular remodeling in idiopathic pulmonary fibrosis (IPF). Our preliminary data demonstrate that N0X4 expression is upregulated in lung fibroblasts (Fbs) isolated from IPF patients; N0X4 expression is induced in pleural mesothelial cells (PMCs) during the process of a mesothelial-to-mesenchymal transition (Project 1) and is regulated by matrix stiffness;miR-31 regulates integrin a5 and RhoA (Project 2), which regulates cellular contractility and reciprocally controls matrix stiffness. Exogenous N0X4 expression activates latent TGF-P, and N0X4-dependent reactive oxygen species (ROS) mediates matrix cross linking in the presence of heme peroxidases. The central hypothesis of this project is that N0X4 mediates myofibroblast differentiation and contractility in IPF, and that targeting of NOX by RNAi approaches or small molecule inhibitors protects against fibrosis in animal models.
Our specific aims are to (1) determine whether lung expression of N0X4 is predictive of disease severity and/or progression in IPF;(2) determine mechanisms of N0X4-dependent H2O2 generation in activation of latent TGF-(3 and in oxidative matrix cross linking that reciprocally contributes to matrix stiffness;(3) determine whether conditional deletion of N0X4 in Fbs and/or PMCs protects against fibrosis in experimental models of lung fibrosis;and (4) determine the efficacy of targeting N0X4 with small molecule inhibitors and/or siRNA in experimental models of lung fibrosis. These studies will inform and support a potential role of N0X4 as a novel therapeutic target in IPF.

Public Health Relevance

This project seeks to identify effective drug therapies for IPF. Specifically, we aim to identify an anti-oxidant therapeutic approach that will be more specific and effective than those in completed or ongoing clinical trials in IPF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL114470-02
Application #
8735180
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
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
Li, Fu Jun; Surolia, Ranu; Li, Huashi et al. (2017) Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis. J Immunol 199:1596-1605
Ge, Jing; Cui, Huachun; Xie, Na et al. (2017) Glutaminolysis Promotes Collagen Translation and Stability via ?-ketoglutarate Mediated mTOR Activation and Proline Hydroxylation. Am J Respir Cell Mol Biol :
Cui, Huachun; Ge, Jing; Xie, Na et al. (2017) miR-34a promotes fibrosis in aged lungs by inducing alveolarepithelial dysfunctions. Am J Physiol Lung Cell Mol Physiol 312:L415-L424
Hough, K P; Chanda, D; Duncan, S R et al. (2017) Exosomes in immunoregulation of chronic lung diseases. Allergy 72:534-544
Sanders, Yan Y; Liu, Hui; Scruggs, Anne M et al. (2017) Epigenetic Regulation of Caveolin-1 Gene Expression in Lung Fibroblasts. Am J Respir Cell Mol Biol 56:50-61
Cui, Huachun; Ge, Jing; Xie, Na et al. (2017) miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence. Am J Respir Cell Mol Biol 56:168-178
de Andrade, Joao A; Luckhardt, Tracy (2017) What Is in a Pattern? That Which We Call Idiopathic Pulmonary Fibrosis by Any Other Pattern Would Behave Alike! Am J Respir Crit Care Med 195:10-12
Xie, Na; Cui, Huachun; Ge, Jing et al. (2017) Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis. Am J Physiol Lung Cell Mol Physiol 313:L834-L844
Surolia, Ranu; Li, Fu Jun; Wang, Zheng et al. (2017) 3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs. JCI Insight 2:e91377

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