Letter abstract
Nature Medicine 15, 1077 - 1081 (2009)
Published online: 23 August 2009 | doi:10.1038/nm.2005
NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury
Louise Hecker1,4, Ragini Vittal1,4, Tamara Jones1, Rajesh Jagirdar1, Tracy R Luckhardt1, Jeffrey C Horowitz1, Subramaniam Pennathur2, Fernando J Martinez1 & Victor J Thannickal1,3
Abstract
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-
1 (TGF-1) 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-1–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.
- Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
- Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
- Present address: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
- These authors contributed equally to this work.
Correspondence to: Victor J Thannickal1,3 e-mail: vjthan@uab.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
In neuroblastic tumours, Schwann cells do not harbour the genetic alterations of neuroblasts but may nevertheless share the same clonal originOncogene Scientific Correspondence
Topical Application of a Peptide Inhibitor of Transforming Growth Factor-β1 Ameliorates Bleomycin-Induced Skin FibrosisJournal of Investigative Dermatology Original Article
MS80, a novel sulfated oligosaccharide, inhibits pulmonary fibrosis by targeting TGF-β1 both in vitro and in vivoActa Pharmacologica Sinica Original Article
See all 5 matches for Research
