An inhibitor of NADPH oxidase-4 attenuates established pulmonary fibrosis in a rodent disease model

• Published in: American journal of respiratory cell and molecular biology Vol. 50; no. 1; pp. 158 - 169
• Main Authors: Jarman, Elizabeth R, Khambata, Valerie S, Cope, Claire, Jones, Peter, Roger, Jan, Ye, Li Yun, Duggan, Nicholas, Head, Denise, Pearce, Andrew, Press, Neil J, Bellenie, Ben, Sohal, Bindi, Jarai, Gabor
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01-01-2014
• Subjects: Acquisitions & mergers; Actins - genetics; Actins - metabolism; Animals; Apoptosis; Blood pressure; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cells, Cultured; Collagen; Collagen Type I - genetics; Collagen Type I - metabolism; Collagen Type III - genetics; Collagen Type III - metabolism; Disease; Enzyme Inhibitors - pharmacology; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Fibronectins - genetics; Fibronectins - metabolism; Gene expression; Genotype & phenotype; Humans; Hypoxia; Idiopathic Pulmonary Fibrosis - genetics; Idiopathic Pulmonary Fibrosis - metabolism; Idiopathic Pulmonary Fibrosis - pathology; Kinases; Laboratory animals; Lung - drug effects; Lung - metabolism; Lung - pathology; Male; Medical prognosis; Mortality; Muscle, Smooth - drug effects; Muscle, Smooth - metabolism; Muscle, Smooth - pathology; Myofibroblasts - drug effects; Myofibroblasts - metabolism; Myofibroblasts - pathology; NADPH Oxidase 4; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Pathogenesis; Pathology; Proteins; Pulmonary arteries; Pulmonary fibrosis; Rats; Rats, Sprague-Dawley; Rodent Diseases - genetics; Rodent Diseases - metabolism; Rodent Diseases - pathology; Rodents; Small Molecule Libraries - pharmacology; Studies; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Up-Regulation - drug effects; Up-Regulation - genetics
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2013-0174oc

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.