Dataset Information

Sestrin-2, a repressor of PDGFR? 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 PDGFR? signalling, and PDGFR? 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 PDGFR? expression via a selective accumulation of intracellular superoxide anions (O2(-)). We also show that SESN2 is overexpressed and PDGFR? 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-PDGFR? 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.

SUBMITTER: Heidler J

PROVIDER: S-EPMC3820261 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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

Heidler Juliana J Fysikopoulos Athanasios A Wempe Frank F Seimetz Michael M Bangsow Thorsten T Tomasovic Ana A Veit Florian F Scheibe Susan S Pichl Alexandra A Weisel Friederike F Lloyd K C Kent KC Jaksch Peter P Klepetko Walter W Weissmann Norbert N von Melchner Harald H

Disease models & mechanisms 20130829 6

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 mainte ...[more]

PMID: 24046361

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Project description:RationaleMatrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction.ObjectivesTo determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples.MethodsMouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury.Measurements and main resultsMice deficient in MMP-9 develop the same degree of cigarette smoke-induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage.ConclusionsThese results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke-induced emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).

Dataset Information

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

Publications

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

Similar Datasets

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