Fibrosis involving the airways, vasculature, alveoli, and pleura is seen, to varying degrees, in a number of clinical syndromes, including asthma, subphenotypes of chronic obstructive pulmonary disease, pulmonary hypertension, and idiopathic pulmonary fibrosis (IPF). IPF is the most enigmatic and fatal of the fibrotic lung disorders. Despite the recent approval of two drugs, survival has not significantly improved. Pulmonary fibrosis represents a complex tissue response to lung injury that involves a number of cell types, mediators, and signaling pathways. In just over the last few years, several new concepts in disease pathogenesis have emerged; these include metabolic reprogramming, epigenetics, immune modulation, macrophage biology and the invasive/apoptosis-resistant phenotype of myofibroblasts (myoFbs). Each of these concepts/paradigms is addressed in this renewal application of this tPPG. Work conducted during Cycle I of this tPPG has validated the pro-fibrotic effects of the reactive oxygen species (ROS)-regenerating enzyme, NADPH oxidase 4 (NOX4), and identified circulating plasma biomarkers of oxidative stress in human subjects with IPF. In Project 1, we will conduct a Phase IIb clinical trial of the safety and efficacy of a NOX1/4 inhibitor in IPF using multiple biomarkers and physiologic measures as primary and secondary end-points. Project 2 will test the hypothesis that redox-metabolic reprogramming of myoFbs accounts for the observed pro-fibrotic effects of NOX4. Based on emerging data on macrophage-myoFb interactions in fibrosis, Project 3 will test the hypothesis that NOX4 modulates macrophage mitochondrial ROS and metabolism to polarize alveolar macrophages to a pro-fibrotic phenotype. Project 4 will test the novel hypothesis that B-cell derived autoantibodies epigenetically reprogram Fbs to an anti-apoptotic phenotype. Together, this tPPG will elucidate critical links between cellular redox control and metabolic reprogramming, uncover novel regulatory mechanisms of macrophage polarization, and illuminate previously unrecognized connections between innate/adaptive immunity, epigenetics and lung fibrosis. Importantly, this tPPG will advance a novel anti-fibrotic drug therapy that more specifically targets redox biology in IPF, which will enable future Phase III clinical trials.

Public Health Relevance

This translational program project will advance a novel therapeutic strategy that addresses redox imbalance and metabolic reprogramming of pro-fibrotic cells, including myofibroblasts, macrophages, and B- lymphocytes, in the development and progression of lung fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL114470-06
Application #
9356774
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Craig, Matt
Project Start
2013-09-16
Project End
2023-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
6
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
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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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