NADPH Oxidase-4 Mediates Myofibroblast Activation and Fibrogenic Responses to Lung Injury

By L. Hecker, R. Vittal, Tamara R. Jones, R. Jagirdar, T. Luckhardt, J. Horowitz, S. Pennathur, F. Martinez, V. Thannickal. Nature Medicine, 2009

818 citations recorded by the source corpus.

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 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 (gp91phox), 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 (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.

Subfields: Immunology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/2dc8dc8304647e34d3c860b7a1d8c93414fc97ec

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. D. Sheppard
2. Kevin K. Kim
3. H. Chapman
4. TA Wynn

In Pulmonary and Respiratory Medicine

1. D. Sheppard
2. TA Wynn
3. Jeremy S. Duffield

Citations in the corpus

• Reciprocal regulation of TGF-β and reactive oxygen species: A perverse cycle for fibrosis (2015, neutral): “…also been shown to mediate TGF-β - induced activation of fi broblasts from kidney, nasal polyss, liver, and heart [92,96,118,202 – 204], although Nox4 was found to function upstream of Smad in cardiac fi broblasts [96] but down-stream of Smad in human lung mesenchymal cells and nasal polys [92,111].”
• Integrating mechanisms of pulmonary fibrosis (2011, background): “NOX4 activity is induced in the lungs of mice after particle phagocytosis and promotes fibrogenesis in two distinct models of lung injury (Hecker et al., 2009).”
• TGF-β1 Signaling and Tissue Fibrosis. (2018, background): “Similarly, targeting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), a TGF-b1-responsive gene, attenuates lung fibrosis at least in part through inhibition of NOX4or ROS-mediated senescence (Hecker et al. 2009).”