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

Juliana Heidler, Athanasios Fysikopoulos, Frank Wempe, Michael Seimetz, Thorsten Bangsow, Ana Tomasovic, Florian Veit, Susan Scheibe, Alexandra Pichl, Friederike Weisel, Kevin C K Lloyd, Peter Jaksch, Walter Klepetko, Norbert Weissmann, Harald Von Melchner

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1378-1387
Number of pages10
JournalDMM Disease Models and Mechanisms
Volume6
Issue number6
DOIs
StatePublished - Nov 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Neuroscience (miscellaneous)

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