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Antioxid Redox Signal. 2019 Feb 22. doi: 10.1089/ars.2019.7742. [Epub ahead of print]

Redox Imbalance in Idiopathic Pulmonary Fibrosis: A Role for Oxidant Cross-Talk Between NOX Enzymes and Mitochondria.

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Maastricht University, 5211, Department of Pharmacology and Toxicology, Maastricht, Limburg, Nicaragua ;
Maastricht University, 5211, Department of Pharmacology and Toxicology, Maastricht, Limburg, Netherlands ;
Maastricht University, 5211, Maastricht, Limburg, Netherlands ;
Maastricht University, Toxicology, Maasstricht, Netherlands ;
University of Vermont, Pathology , D205 Given Medical Building , 89 Beaumont Avenue , Burlington , Burlington, Vermont, United States , 05405 ;


Idiopathic pulmonary fibrosis (IPF) is a progressive age-related lung disease with a median survival of only 3 years after diagnosis. The pathogenic mechanisms behind IPF are not clearly understood and current therapeutic approaches have not been successful in improving disease outcomes. Recent advances: IPF is characterized by increased production of reactive oxygen species (ROS), primarily by NADPH oxidases (NOXes) and mitochondria, as well as altered antioxidant defenses. Recent studies have identified the NOX isoform NOX4 as a key player in various important aspects of IPF pathology. In addition, mitochondrial dysfunction is thought to enhance pathological features of IPF, in part by increasing mitochondrial ROS production and altering cellular metabolism. Recent findings indicate reciprocal interactions between NOX enzymes and mitochondria, which affect regulation of NOX activity as well as mitochondrial function and mtROS production, and collectively promote epithelial injury and profibrotic signaling. Critical Issues and Future Directions: The precise molecular mechanisms by which ROS from NOX or mitochondria contribute to IPF pathology are not known. This review will summarize current knowledge with respect to the various aspects of ROS imbalance in the context of IPF and its proposed roles in disease development, with specific emphasis on the importance of inappropriate NOX activation, mitochondrial dysfunction, and the emerging evidence of NOX-mitochondria crosstalk as important drivers in IPF pathobiology.


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