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

Lehmann, Mareike; Korfei, Martina; Mutze, Kathrin; Klee, Stephan; Skronska-Wasek, Wioletta; Alsafadi, Hani N. LU ; Ota, Chiharu; Costa, Ana Rita; Schiller, Herbert B and Lindner, Michael, et al. (2017) In European Respiratory Journal1988-01-01+01:00 50. p.1-15
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... (More)

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.

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keywords
Journal Article
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European Respiratory Journal1988-01-01+01:00
volume
50
pages
1 - 15
publisher
Eur Respiratory Soc
external identifiers
  • scopus:85027886209
ISSN
1399-3003
DOI
10.1183/13993003.02367-2016
language
English
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no
id
b93c7193-ef19-4ef5-ba08-895df42f2d5e
date added to LUP
2017-08-15 15:18:26
date last changed
2018-01-07 12:14:59
@article{b93c7193-ef19-4ef5-ba08-895df42f2d5e,
  abstract     = {<p>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.</p>},
  articleno    = {1602367},
  author       = {Lehmann, Mareike and Korfei, Martina and Mutze, Kathrin and Klee, Stephan and Skronska-Wasek, Wioletta and Alsafadi, Hani N. and Ota, Chiharu and Costa, Ana Rita and Schiller, Herbert B and Lindner, Michael and Wagner, Darcy E and Günther, Andreas and Königshoff, Melanie},
  issn         = {1399-3003},
  keyword      = {Journal Article},
  language     = {eng},
  pages        = {1--15},
  publisher    = {Eur Respiratory Soc},
  series       = {European Respiratory Journal1988-01-01+01:00},
  title        = {Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo},
  url          = {http://dx.doi.org/10.1183/13993003.02367-2016},
  volume       = {50},
  year         = {2017},
}