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      NADPH oxidase-dependent redox signaling in TGF-β-mediated fibrotic responses ☆

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          Abstract

          Uncontrolled fibrosis in organs like heart, kidney, liver and lung is detrimental and may lead to end-stage organ failure. Currently there is no effective treatment for fibrotic disorders. Transforming growth factor (TGF)-β has a fundamental role in orchestrating the process of fibrogenesis; however, interventions directly targeting TGF-β would have undesired systemic side effects due to the multiple physiological functions of TGF-β. Further characterization of the downstream signaling pathway(s) involved in TGF-β-mediated fibrosis may lead to discovery of novel treatment strategies for fibrotic disorders. Accumulating evidence suggests that Nox4 NADPH oxidase may be an important downstream effector in mediating TGF-β-induced fibrosis, while NADPH oxidase-dependent redox signaling may in turn regulate TGF-β/Smad signaling in a feed-forward manner. It is proposed that pharmacological inhibition of the Nox4 function may represent a novel approach in treatment of fibrotic disorders.

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          Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases.

          Thomas Wynn (2007)
          Fibroproliferative diseases, including the pulmonary fibroses, systemic sclerosis, liver cirrhosis, cardiovascular disease, progressive kidney disease, and macular degeneration, are a leading cause of morbidity and mortality and can affect all tissues and organ systems. Fibrotic tissue remodeling can also influence cancer metastasis and accelerate chronic graft rejection in transplant recipients. Nevertheless, despite its enormous impact on human health, there are currently no approved treatments that directly target the mechanism(s) of fibrosis. The primary goals of this Review series on fibrotic diseases are to discuss some of the major fibroproliferative diseases and to identify the common and unique mechanisms of fibrogenesis that might be exploited in the development of effective antifibrotic therapies.
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            NADPH Oxidase-4 Mediates Myofibroblast Activation and Fibrogenic Responses to Lung Injury

            Louise Hecker, Ragini Vittal, Tamara Jones … (2009)
            The NADPH oxidase (NOX) family of enzymes, which catalyze the reduction of O2 to form reactive oxygen species (ROS), have increased in number during eukaryotic evolution1,2. Seven isoforms of the NOX gene family have been identified in mammals; however, specific roles of NOX enzymes in mammalian physiology and pathophysiology have not been fully elucidated3,4. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants5,6. The prototypical member of this family, NOX2 (gp91 phox ), is expressed in phagocytic cells and mediates microbicidal activities7,8. Here, we report a role for the NOX4 isoform in tissue repair functions of myofibroblasts and fibrogenesis. Transforming growth factor-β1 (TGF-β1) induces NOX4 expression in lung mesenchymal cells by a SMAD3-dependent mechanism. NOX4-dependent generation of hydrogen peroxide (H2O2) is required for TGF-β1-induced myofibroblast differentiation, extracellular matrix (ECM) production, and contractility. NOX4 is upregulated in lungs of mice subjected to non-infectious injury and in human idiopathic pulmonary fibrosis (IPF). Genetic or pharmacologic targeting of NOX4 abrogates fibrogenesis in two different murine models of lung injury. These studies support a novel function for NOX4 in tissue fibrogenesis and provide proof-of-concept for therapeutic targeting of NOX4 in recalcitrant fibrotic disorders.
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              Evidence that fibroblasts derive from epithelium during tissue fibrosis.

              Theodore M Danoff, Masayuki Iwano, David Plieth … (2002)
              Interstitial fibroblasts are principal effector cells of organ fibrosis in kidneys, lungs, and liver. While some view fibroblasts in adult tissues as nothing more than primitive mesenchymal cells surviving embryologic development, they differ from mesenchymal cells in their unique expression of fibroblast-specific protein-1 (FSP1). This difference raises questions about their origin. Using bone marrow chimeras and transgenic reporter mice, we show here that interstitial kidney fibroblasts derive from two sources. A small number of FSP1(+), CD34(-) fibroblasts migrate to normal interstitial spaces from bone marrow. More surprisingly, however, FSP1(+) fibroblasts also arise in large numbers by local epithelial-mesenchymal transition (EMT) during renal fibrogenesis. Both populations of fibroblasts express collagen type I and expand by cell division during tissue fibrosis. Our findings suggest that a substantial number of organ fibroblasts appear through a novel reversal in the direction of epithelial cell fate. As a general mechanism, this change in fate highlights the potential plasticity of differentiated cells in adult tissues under pathologic conditions.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Redox Biol
                Journal ID (iso-abbrev): Redox Biol
                Title: Redox Biology
                Publisher: Elsevier
                ISSN (Electronic): 2213-2317
                Publication date PMC-release: 20 January 2014
                Publication date (Electronic): 20 January 2014
                Publication date Collection: 2014
                Volume: 2
                Pages: 267-272
                Affiliations
                [a ]Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China
                [b ]Centre for Eye Research Australia, University of Melbourne, VIC 3002, Australia
                [c ]Department of Ophthalmology, University of Melbourne, VIC 3002, Australia
                Author notes
                [* ]Corresponding author. Tel.: +86 531 8216 9257; fax: +86 531 8616 9356. fjiang@ 123456sdu.edu.cn
                [** ]Corresponding author. Centre for Eye Research Australia (CERA), 1/32, Gisborne Street, East Melbourne, VIC 3002, Australia. Tel.: +61 3 9929 8360; fax: +61 3 9416 0926. elsa.chan@ 123456unimelb.edu.au
                Article
                Publisher ID: S2213-2317(14)00027-5
                DOI: 10.1016/j.redox.2014.01.012
                PMC ID: 3909817
                PubMed ID: 24494202
                SO-VID: 4217a09d-5c38-45c7-aa8f-1ca0b0949d5c
                Copyright © © 2014 The Authors
                History
                Date received : 13 January 2014
                Date accepted : 14 January 2014
                Categories
                Subject: Graphical Review

                Keywords: nox4,redox signaling,fibrosis,transforming growth factor-β,nadph oxidase
                Data availability:
                Keywords: nox4, redox signaling, fibrosis, transforming growth factor-β, nadph oxidase

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