Reactive Oxygen Species as Signaling Molecules in the Development of Lung Fibrosis

Publication date: Available online 10 October 2017
Source:Translational Research
Author(s): Francisco J. Gonzalez-Gonzalez, Navdeep Chandel, Manu Jain, GR Scott Budinger
Pulmonary 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 NADPH oxidase-generated reactive oxygen species (ROS) play a signaling role to enhance TGF-β signaling and promote fibrosis. This purpose of this review is to review ROS signaling downstream of 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.



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