NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury.
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-beta1 (TGF-beta1) 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-beta1-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.
Hecker
Louise
L
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Vittal
Ragini
R
Jones
Tamara
T
Jagirdar
Rajesh
R
Luckhardt
Tracy R
TR
Horowitz
Jeffrey C
JC
Pennathur
Subramaniam
S
Martinez
Fernando J
FJ
Thannickal
Victor J
VJ
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C422943:Nox4 protein, mouse
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