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

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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.; Ota, Chiharu; Costa, Ana Rita; Schiller, Herbert B; Lindner, Michael; Wagner, Darcy E; Günther, Andreas; Königshoff, Melanie.

I: European Respiratory Journal, Vol. 50, 1602367, 08.2017, s. 1-15.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Lehmann, M, Korfei, M, Mutze, K, Klee, S, Skronska-Wasek, W, Alsafadi, HN, Ota, C, Costa, AR, Schiller, HB, Lindner, M, Wagner, DE, Günther, A & Königshoff, M 2017, 'Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo', European Respiratory Journal, vol. 50, 1602367, s. 1-15. https://doi.org/10.1183/13993003.02367-2016

APA

CBE

Lehmann M, Korfei M, Mutze K, Klee S, Skronska-Wasek W, Alsafadi HN, Ota C, Costa AR, Schiller HB, Lindner M, Wagner DE, Günther A, Königshoff M. 2017. Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo. European Respiratory Journal. 50:1-15. https://doi.org/10.1183/13993003.02367-2016

MLA

Vancouver

Author

Lehmann, Mareike ; Korfei, Martina ; Mutze, Kathrin ; Klee, Stephan ; Skronska-Wasek, Wioletta ; Alsafadi, Hani N. ; Ota, Chiharu ; Costa, Ana Rita ; Schiller, Herbert B ; Lindner, Michael ; Wagner, Darcy E ; Günther, Andreas ; Königshoff, Melanie. / Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo. I: European Respiratory Journal. 2017 ; Vol. 50. s. 1-15.

RIS

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, Ana Rita

AU - Schiller, Herbert B

AU - Lindner, Michael

AU - Wagner, Darcy E

AU - Günther, Andreas

AU - Königshoff, Melanie

N1 - Copyright ©ERS 2017.

PY - 2017/8

Y1 - 2017/8

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 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.

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 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.

KW - Journal Article

U2 - 10.1183/13993003.02367-2016

DO - 10.1183/13993003.02367-2016

M3 - Article

VL - 50

SP - 1

EP - 15

JO - European Respiratory Journal

T2 - European Respiratory Journal

JF - European Respiratory Journal

SN - 1399-3003

M1 - 1602367

ER -