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 Journal
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.
(Less)
- author
- 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. (More)
- Lehmann, Mareike
; Korfei, Martina
; Mutze, Kathrin
; Klee, Stephan
; Skronska-Wasek, Wioletta
; Alsafadi, Hani N.
LU
; Ota, Chiharu
; Costa, Ana Rita
; Schiller, Herbert B
; Lindner, Michael
; Wagner, Darcy E
LU
; Günther, Andreas
and Königshoff, Melanie
(Less)
- publishing date
- 2017-08
- type
- Contribution to journal
- publication status
- published
- keywords
- Journal Article
- in
- European Respiratory Journal
- volume
- 50
- article number
- 1602367
- pages
- 1 - 15
- publisher
- European Respiratory Society
- external identifiers
-
- pmid:28775044
- scopus:85027886209
- ISSN
- 1399-3003
- DOI
- 10.1183/13993003.02367-2016
- language
- English
- LU publication?
- no
- id
- b93c7193-ef19-4ef5-ba08-895df42f2d5e
- date added to LUP
- 2017-08-15 15:18:26
- date last changed
- 2024-04-14 16:21:54
@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>}},
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}},
keywords = {{Journal Article}},
language = {{eng}},
pages = {{1--15}},
publisher = {{European Respiratory Society}},
series = {{European Respiratory Journal}},
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}},
doi = {{10.1183/13993003.02367-2016}},
volume = {{50}},
year = {{2017}},
}