NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury

Louise Hecker, Ragini Vittal, Tamara Jones, Rajesh Jagirdar, Tracy R. Luckhardt, Jeffrey C. Horowitz, Subramaniam Pennathur, Fernando J. Martinez, Victor J. Thannickal

Research output: Contribution to journalArticle

499 Scopus citations

Abstract

Members of the NADPH oxidase (NOX) family of enzymes, which catalyze the reduction of O 2 to reactive oxygen species, have increased in number during eukaryotic evolution. 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 elucidated. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants. The prototypical member of this family, NOX-2 (gp91 phox), is expressed in phagocytic cells and mediates microbicidal activities. 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 (H 2 O 2) 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.

Original languageEnglish (US)
Pages (from-to)1077-1081
Number of pages5
JournalNature Medicine
Volume15
Issue number9
DOIs
StatePublished - Sep 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Hecker, L., Vittal, R., Jones, T., Jagirdar, R., Luckhardt, T. R., Horowitz, J. C., Pennathur, S., Martinez, F. J., & Thannickal, V. J. (2009). NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nature Medicine, 15(9), 1077-1081. https://doi.org/10.1038/nm.2005