TY - JOUR
T1 - Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo
AU - Lehmann, Mareike
AU - Korfei, Martina
AU - Mutze, Kathrin
AU - Klee, Stephan
AU - Skronska-Wasek, Wioletta
AU - Alsafadi, Hani N.
AU - Ota, Chiharu
AU - Costa, Rita
AU - Schiller, Herbert B.
AU - Lindner, Michael
AU - Wagner, Darcy E.
AU - Günther, Andreas
AU - Königshoff, Melanie
N1 - Funding Information:
Support statement: This work was funded by grants from the German Center of Lung Research and a W2/W3 professorship award from the Helmholtz Association to M. Königshoff. D.E. Wagner is supported by a Whitaker International Scholar Fellowship and the Helmholtz Munich postdoctoral program. Funding information for this article has been deposited with the Crossref Funder Registry.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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 senescenceassociated 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.
AB - 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 senescenceassociated 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.
UR - http://www.scopus.com/inward/record.url?scp=85027886209&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85027886209&partnerID=8YFLogxK
U2 - 10.1183/13993003.02367-2016
DO - 10.1183/13993003.02367-2016
M3 - Article
C2 - 28775044
AN - SCOPUS:85027886209
VL - 50
JO - European Respiratory Journal
JF - European Respiratory Journal
SN - 0903-1936
IS - 2
ER -