Members of the NADPH oxidase (NOX) family of enzymes, which catalyze the reduction of O2 to reactive oxygen species, 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, NOX-2 (gp91phox), 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 NOX-4 expression in lung mesenchymal cells via SMAD-3, a receptor-regulated protein that modulates gene transcription. NOX-4–dependent generation of hydrogen peroxide (H2O2) is required for TGF-β1–induced myofibroblast differentiation, extracellular matrix (ECM) production and contractility. NOX-4 is upregulated in lungs of mice subjected to noninfectious injury and in cases of human idiopathic pulmonary fibrosis (IPF). Genetic or pharmacologic targeting of NOX-4 abrogates fibrogenesis in two murine models of lung injury. These studies support a function for NOX4 in tissue fibrogenesis and provide proof of concept for therapeutic targeting of NOX-4 in recalcitrant fibrotic disorders.
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We thank D. Lambeth, Department of Biochemistry, Emory University, for providing the rabbit polyclonal antibody to NOX-4 and A. Jesaitis, Department of Microbiology, Montana State University, for the mouse monoclonal antibody to NOX-2. We thank D. Arenberg, Department of Internal Medicine, University of Michigan, for providing primary lung mesenchymal cells from human subjects with IPF (IPF-MCs). This work was supported by grants from the US National Institutes of Health R01 HL067967 (to V.J.T.) and K08 HL081059 (to J.C.H.) and by a National Institutes of Health–sponsored Lung Tissue Research Consortium grant, N01 HR046162 (to F.J.M.).
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Hecker, L., Vittal, R., Jones, T. et al. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med 15, 1077–1081 (2009). https://doi.org/10.1038/nm.2005
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