Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD is caused by chronic exposure to cigarette smoke and/or other environmental pollutants that are believed to induce reactive oxygen species (ROS) that gradually disrupt signalling pathways respo...

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Published in:Disease models & mechanisms 2013-11, Vol.6 (6), p.1378-1387
Main Authors: Heidler, Juliana, Fysikopoulos, Athanasios, Wempe, Frank, Seimetz, Michael, Bangsow, Thorsten, Tomasovic, Ana, Veit, Florian, Scheibe, Susan, Pichl, Alexandra, Weisel, Friederike, Lloyd, K C Kent, Jaksch, Peter, Klepetko, Walter, Weissmann, Norbert, von Melchner, Harald
Format: Article
Language:English
Subjects:
Animals
Humans
Lung - metabolism
Mice
Mice, Knockout
Nuclear Proteins - genetics
Nuclear Proteins - physiology
Pulmonary Disease, Chronic Obstructive - metabolism
Pulmonary Emphysema - etiology
Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors
Receptor, Platelet-Derived Growth Factor beta - metabolism
Signal Transduction - physiology
Smoke
Superoxides - metabolism
Up-Regulation
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Summary:Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD is caused by chronic exposure to cigarette smoke and/or other environmental pollutants that are believed to induce reactive oxygen species (ROS) that gradually disrupt signalling pathways responsible for maintaining lung integrity. Here we identify the antioxidant protein sestrin-2 (SESN2) as a repressor of PDGFRβ signalling, and PDGFRβ signalling as an upstream regulator of alveolar maintenance programmes. In mice, the mutational inactivation of Sesn2 prevents the development of cigarette-smoke-induced pulmonary emphysema by upregulating PDGFRβ expression via a selective accumulation of intracellular superoxide anions (O2(-)). We also show that SESN2 is overexpressed and PDGFRβ downregulated in the emphysematous lungs of individuals with COPD and to a lesser extent in human lungs of habitual smokers without COPD, implicating a negative SESN2-PDGFRβ interrelationship in the pathogenesis of COPD. Taken together, our results imply that SESN2 could serve as both a biomarker and as a drug target in the clinical management of COPD.
ISSN:1754-8403
1754-8411
DOI:10.1242/dmm.013482