Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD
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 pathwa...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2013-11-01
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| Series: | Disease Models & Mechanisms |
| Online Access: | http://dmm.biologists.org/content/6/6/1378 |
| _version_ | 1819127010594652160 |
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| 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 |
| author_facet | 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 |
| author_sort | Juliana Heidler |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T08:05:08Z |
| format | Article |
| id | doaj.art-d0798f2f4197457a84ffe11f8b2917d4 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-22T08:05:08Z |
| publishDate | 2013-11-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-d0798f2f4197457a84ffe11f8b2917d42022-12-21T18:33:10ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112013-11-01661378138710.1242/dmm.013482013482Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPDJuliana HeidlerAthanasios FysikopoulosFrank WempeMichael SeimetzThorsten BangsowAna TomasovicFlorian VeitSusan ScheibeAlexandra PichlFriederike WeiselK. C. Kent LloydPeter JakschWalter KlepetkoNorbert WeissmannHarald von MelchnerSUMMARY 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.http://dmm.biologists.org/content/6/6/1378 |
| spellingShingle | 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 Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD Disease Models & Mechanisms |
| title | Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD |
| title_full | Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD |
| title_fullStr | Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD |
| title_full_unstemmed | Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD |
| title_short | Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD |
| title_sort | sestrin 2 a repressor of pdgfrβ signalling promotes cigarette smoke induced pulmonary emphysema in mice and is upregulated in individuals with copd |
| url | http://dmm.biologists.org/content/6/6/1378 |
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