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 induc
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.
show moreshow less

Metadaten
Author:Juliana Heidler, Athanasios Fysikopoulos, Frank Wempe, Michael Seimetz, Thorsten Bangsow, Ana Tomasovic, Florian Veit, Susan Scheibe, Alexandra Pichl, Friederike Weisel, K. C. Kent Lloyd, Peter Jaksch, Walter Klepetko, Norbert Weißmann, Harald von Melchner
URN:urn:nbn:de:hebis:30:3-342195
DOI:http://dx.doi.org/10.1242/dmm.013482
ISSN:1754-8403
ISSN:1754-8411
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=24046361
Parent Title (English):Disease models & mechanisms
Publisher:Company of Biologists Limited
Place of publication:Cambridge
Document Type:Article
Language:English
Date of Publication (online):2014/06/18
Date of first Publication:2013/11/07
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2014/06/18
Tag:COPD; KGF; PDGFRβ; ROS; Sestrin 2
Volume:6
Issue:6
Pagenumber:10
First Page:1378
Last Page:1387
Note:
Copyright © 2013. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
HeBIS PPN:365575526
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0

$Rev: 11761 $