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LSC - 2017 - Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo

Mareike Lehmann, Kathrin Mutze, Martina Korfei, Stephan Klee, Darcy Wagner, Rita Costa, Herbert Schiller, Andreas Günther, Melanie Königshoff
European Respiratory Journal 2017 50: PA3471; DOI: 10.1183/1393003.congress-2017.PA3471
Mareike Lehmann
1Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians Universität, Member of the German Center for Lung Research (DZL), Munich, Germany
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Kathrin Mutze
1Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians Universität, Member of the German Center for Lung Research (DZL), Munich, Germany
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Martina Korfei
2Dept of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig-UniversitÄt Giessen, Member of the German Center for Lung Research (DZL), Giessen, Germany
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Stephan Klee
1Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians Universität, Member of the German Center for Lung Research (DZL), Munich, Germany
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Darcy Wagner
1Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians Universität, Member of the German Center for Lung Research (DZL), Munich, Germany
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Rita Costa
1Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians Universität, Member of the German Center for Lung Research (DZL), Munich, Germany
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Herbert Schiller
1Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians Universität, Member of the German Center for Lung Research (DZL), Munich, Germany
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Andreas Günther
1Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians Universität, Member of the German Center for Lung Research (DZL), Munich, Germany
4Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein, Germany
5European IPF Network and European IPF Registry
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Melanie Königshoff
6Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians UniversitÄt, Member of the German Center for Lung Research (DZL), Munich, Germany
7Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Denver, CO, USA
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating, age-related lung disease with limited therapeutic options. Aging-related mechanisms such as cellular senescence have been proposed as a pathogenic driver. The lung epithelium that contains progenitor cells such as alveolar epithelial type II (ATII) cells represents a major site of tissue injury in IPF. Senescence of ATII cells is likely detrimental to lung repair and regeneration. ATII cell senescence and its potential effects in IPF, however, remain poorly understood. Here we analyzed epithelial cell senescence and its effects on pulmonary fibrosis. Gene set enrichment analysis revealed enrichment of senescence associated genes in ATII cells from experimental lung fibrosis. Fibrotic ATII cells exhibited increased senescence-associated ß-Galactosidase staining as analyzed by FACS. This was accompanied by enhanced gene expression of senescence-associated p16 and p21. Moreover, proteomic analysis of ATII supernatants showed secretion of factors associated with the senescence associated secretome (SASP). Importantly, human IPF lungs showed increased senescence-associated p16 gene and protein expression as compared to donors, an effect which was recapitulated in phATII cells. Pharmacological depletion of senescent cells with senolytic drugs from fibrotic 3D lung tissue cultures reduced fibrotic marker gene expression and increased the ATII cell marker surfactant protein C (Sftpc).In summary, fibrotic ATII cells exhibit increased senescence, which is accompanied by the secretion of SASP factors. Senolytic treatment increased ATII cell markers and decreased fibrotic gene expression, suggesting that senescence contributes to IPF pathogenesis.

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LSC - 2017 - Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo
Mareike Lehmann, Kathrin Mutze, Martina Korfei, Stephan Klee, Darcy Wagner, Rita Costa, Herbert Schiller, Andreas Günther, Melanie Königshoff
European Respiratory Journal Sep 2017, 50 (suppl 61) PA3471; DOI: 10.1183/1393003.congress-2017.PA3471

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LSC - 2017 - Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo
Mareike Lehmann, Kathrin Mutze, Martina Korfei, Stephan Klee, Darcy Wagner, Rita Costa, Herbert Schiller, Andreas Günther, Melanie Königshoff
European Respiratory Journal Sep 2017, 50 (suppl 61) PA3471; DOI: 10.1183/1393003.congress-2017.PA3471
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