An Inhibitor of NADPH Oxidase-4 Attenuates Established Pulmonary Fibrosis in a Rodent Disease Model

Aug 28, 2013American journal of respiratory cell and molecular biology

A blocker of a specific enzyme reduces lung scarring in a rodent disease model

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Abstract

Nox4 is up-regulated in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and contributes to disease progression.

Increased oxidative stress from an oxidant-antioxidant imbalance is thought to play a role in the progression of IPF.
Nox4, a source of reactive oxygen species, is found to be constitutively active and elevated in both human IPF lungs and a rodent model of pulmonary fibrosis.
Targeting Nox4 with a small molecule inhibitor reduces the expression of key extracellular matrix components, such as collagen and fibronectin, associated with fibrosis.
Inhibition of Nox4 also diminishes the up-regulation of fibrotic pathways linked to TGF-β1, a major mediator of fibrosis.
The findings suggest that targeting Nox4 could be a potential therapeutic strategy for managing pulmonary fibrosis.

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Idiopathic pulmonary fibrosis is a chronic progressive disease of increasing prevalence for which there is no effective therapy. Increased oxidative stress associated with an oxidant-antioxidant imbalance is thought to contribute to disease progression. NADPH oxidases (Nox) are a primary source of reactive oxygen species within the lung and cardiovascular system. We demonstrate that the Nox4 isoform is up-regulated in the lungs of patients with IPF and in a rodent model of bleomycin-induced pulmonary fibrosis and vascular remodeling. Nox4 is constitutively active, and therefore increased expression levels are likely to contribute to disease pathology. Using a small molecule Nox4/Nox1 inhibitor, we demonstrate that targeting Nox4 results in attenuation of an established fibrotic response, with reductions in gene transcripts for the extracellular matrix components collagen 1α1, collagen 3α1, and fibronectin and in principle pathway components associated with pulmonary fibrosis and hypoxia-mediated vascular remodeling: transforming growth factor (TGF)-β1, plasminogen activator inhibitor-1, hypoxia-inducible factor, and Nox4. TGF-β1 is a principle fibrotic mediator responsible for inducing up-regulation of profibrotic pathways associated with disease pathology. Using normal human lung-derived primary fibroblasts, we demonstrate that inhibition of Nox4 activity using a small molecule antagonist attenuates TGF-β1-mediated up-regulation in expression of profibrotic genes and inhibits the differentiation of fibroblast to myofibroblasts, that is associated with up-regulation in smooth muscle actin and acquisition of a contractile phenotype. These studies support the view that targeting Nox4 may provide a therapeutic approach for attenuating pulmonary fibrosis.

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An Inhibitor of NADPH Oxidase-4 Attenuates Established Pulmonary Fibrosis in a Rodent Disease Model

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