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Journal article
Transforming growth factor 1 (TGF1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis
The Journal of biological chemistry, v 292(25), pp 10490-10519
23 Jun 2017
PMID: 28389561
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive clinical syndrome of fatal outcome. The lack of information about the signaling pathways that sustain fibrosis and the myofibroblast phenotype has prevented the development of targeted therapies for IPF. Our previous study showed that isolated fibrogenic lung fibroblasts have high endogenous levels of the hyaluronan receptor, CD44V6 (CD44 variant containing exon 6), which enhances the TGF1 autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts. NADPH oxidase 4 (NOX4) enzyme, which catalyzes the reduction of O-2 to hydrogen peroxide (H2O2), has been implicated in the cardiac and lung myofibroblast phenotype. However, whether CD44V6 regulates NOX4 to mediate tissue repair and fibrogenesis is not well-defined. The present study assessed the mechanism of how TGF--1-induced CD44V6 regulates the NOX4/reactive oxygen species (ROS) signaling that mediates the myofibroblast differentiation. Specifically, we found that NOX4/ROS regulates hyaluronan synthesis and the transcription of CD44V6 via an effect upon AP-1 activity. Further, CD44V6 is part of a positive-feedback loop with TGF1/TGFRI signaling that acts to increase NOX4/ROS production, which is required for myofibroblast differentiation, myofibroblast differentiation, myofibroblast extracellular matrix production, myofibroblast invasion, and myofibroblast contractility. Both NOX4 and CD44v6 are up-regulated in the lungs of mice subjected to experimental lung injury and in cases of human IPF. Genetic (CD44v6 shRNA) or a small molecule inhibitor (CD44v6 peptide) targeting of CD44v6 abrogates fibrogenesis in murine models of lung injury. These studies support a function for CD44V6 in lung fibrosis and offer proof of concept for therapeutic targeting of CD44V6 in lung fibrosis disorders.
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Details
- Title
- Transforming growth factor 1 (TGF1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis
- Creators
- Shibnath Ghatak - From the Department of Regenerative Medicine and Cell Biology.Vincent C. Hascall - Cleveland ClinicRoger R. Markwald - From the Department of Regenerative Medicine and Cell Biology.Carol Feghali-Bostwick - the Division of Rheumatology and Immunology, Department of Medicine, and.Carol M. Artlett - Drexel UniversityMonika Gooz - Medical University of South CarolinaGalina S. Bogatkevich - the Division of Rheumatology and Immunology, Department of Medicine, and.Ilia Atanelishvili - the Division of Rheumatology and Immunology, Department of Medicine, and.Richard M. Silver - the Division of Rheumatology and Immunology, Department of Medicine, and.Jeanette Wood - GenkyotexVictor J. Thannickal - University of Alabama at BirminghamSuniti Misra - From the Department of Regenerative Medicine and Cell Biology.
- Publication Details
- The Journal of biological chemistry, v 292(25), pp 10490-10519
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- Number of pages
- 30
- Grant note
- P30GM103342 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) 1 R01HL113325; 1 P01HL107147 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 1RO1 (HL33756); P30 GM103342-03; 5P20GM103499-16; AHA16GRNT31330032; 1P20 GM103444 / NIH Grants; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 5P30GM103339-03 / pilot project award from the COBRE in Lipidomics and Pathobiology (NIH Grant) at the Medical University of South Carolina; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA S10OD018113 / OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 1R03CA167722-01A1 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL033756 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) I01BX003056 / Veterans Affairs; US Department of Veterans Affairs P30 CA138313 / Cell and Molecular Imaging Shared Resource, Hollings Cancer Center, Medical University of South Carolina (NIH Grant) R03CA167722 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) S10 OD018113 / Shared Instrumentation Grant
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000404115400013
- Scopus ID
- 2-s2.0-85021670769
- Other Identifier
- 991019168444504721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology