• Francisco J Gonzalez-Gonzalez, Navdeep S Chandel, Manu Jain, and BudingerG R ScottGRSDivision of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Ill. Electronic address: s-buding@northwestern.edu..
• Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Ill.
• Transl Res. 2017 Dec 1; 190: 616861-68.

AbstractPulmonary fibrosis is a relatively rare but devastating disease characterized by the excessive deposition of extracellular matrix. The increased matrix results in reduced lung compliance and increased work of breathing, while the obliteration of alveolar-capillary structures can result in hypoxemia and pulmonary hypertension, which manifests clinically as worsening shortness of breath, respiratory failure, and death. Unbiased genome-wide association studies combined with animal models suggest that damage to the alveolar epithelium is the initiating factor in pulmonary fibrosis. This epithelial injury leads to the activation and proliferation of myofibroblasts that secrete extracellular matrix proteins characteristic of fibrosis. The best described molecular link between alveolar epithelial dysfunction and myofibroblast activation and proliferation is the profibrotic cytokine transforming growth factor-β (TGF-β). We and others have found that mitochondrial and NAD(P)H oxidase-generated reactive oxygen species (ROS) play a signaling role to enhance TGF-β signaling and promote fibrosis. The purpose of this article is to review how ROS signaling leads to the activation of TGF-β. We suggest that an improved understanding of these pathways might explain the failure of nonselective antioxidants to improve outcomes in patients with pulmonary fibrosis and might identify novel targets for therapy.Published by Elsevier Inc.

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