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Eur Respir J. 2017 Aug 3;50(2). pii: 1602367. doi: 10.1183/13993003.02367-2016. Print 2017 Aug.

Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo.

Author information

1
Comprehensive 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.
2
Dept 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.
3
Center for Thoracic Surgery, Asklepios Biobank for Lung Diseases, Comprehensive Pneumology Center, Asklepios Clinic Munich-Gauting, Munich, Germany.
4
Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein, Germany.
5
European IPF Network and European IPF Registry.
6
Comprehensive 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 melanie.koenigshoff@ucdenver.edu.
7
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Denver, CO, USA.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor prognosis and limited therapeutic options. The incidence of IPF increases with age, and ageing-related mechanisms such as cellular senescence have been proposed as pathogenic drivers. The lung alveolar epithelium represents a major site of tissue injury in IPF and senescence of this cell population is probably detrimental to lung repair. However, the potential pathomechanisms of alveolar epithelial cell senescence and the impact of senolytic drugs on senescent lung cells and fibrosis remain unknown. Here we demonstrate that lung epithelial cells exhibit increased P16 and P21 expression as well as senescence-associated β-galactosidase activity in experimental and human lung fibrosis tissue and primary cells.Primary fibrotic mouse alveolar epithelial type (AT)II cells secreted increased amounts of senescence-associated secretory phenotype (SASP) factors in vitro, as analysed using quantitative PCR, mass spectrometry and ELISA. Importantly, pharmacological clearance of senescent cells by induction of apoptosis in fibrotic ATII cells or ex vivo three-dimensional lung tissue cultures reduced SASP factors and extracellular matrix markers, while increasing alveolar epithelial markers.These data indicate that alveolar epithelial cell senescence contributes to lung fibrosis development and that senolytic drugs may be a viable therapeutic option for IPF.

PMID:
28775044
PMCID:
PMC5593348
DOI:
10.1183/13993003.02367-2016
[Indexed for MEDLINE]
Free PMC Article

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