title: Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD.
abstract: 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.
authors.affiliation: Department of Molecular Haematology, Goethe University Medical School, D-60590 Frankfurt am Main, Germany.
authors.forename: Juliana
authors.initials: J
authors.lastname: Heidler
authors.forename: Athanasios
authors.initials: A
authors.lastname: Fysikopoulos
authors.forename: Frank
authors.initials: F
authors.lastname: Wempe
authors.forename: Michael
authors.initials: M
authors.lastname: Seimetz
authors.forename: Thorsten
authors.initials: T
authors.lastname: Bangsow
authors.forename: Ana
authors.initials: A
authors.lastname: Tomasovic
authors.forename: Florian
authors.initials: F
authors.lastname: Veit
authors.forename: Susan
authors.initials: S
authors.lastname: Scheibe
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pichl
authors.forename: Friederike
authors.initials: F
authors.lastname: Weisel
authors.forename: K C Kent
authors.initials: KC
authors.lastname: Lloyd
authors.forename: Peter
authors.initials: P
authors.lastname: Jaksch
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Harald
authors.initials: H
authors.lastname: von Melchner
mesh_terms: D000818:Animals; D006801:Humans; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010544:Peroxidases; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D011656:Pulmonary Emphysema / Q000209:etiology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D012906:Smoke; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation; D000084622:Sestrins
chemical_list: D009687:Nuclear Proteins; D010544:Peroxidases; D020797:Receptor, Platelet-Derived Growth Factor beta; D012906:Smoke; D013481:Superoxides; C465398:SESN2 protein, human; D000084622:Sestrins; C529380:Sesn2 protein, mouse
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