RT Journal Article
SR Electronic
T1 Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis <em>ex vivo</em>
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1602367
DO 10.1183/13993003.02367-2016
VO 50
IS 2
A1 Lehmann, Mareike
A1 Korfei, Martina
A1 Mutze, Kathrin
A1 Klee, Stephan
A1 Skronska-Wasek, Wioletta
A1 Alsafadi, Hani N.
A1 Ota, Chiharu
A1 Costa, Rita
A1 Schiller, Herbert B.
A1 Lindner, Michael
A1 Wagner, Darcy E.
A1 Günther, Andreas
A1 Königshoff, Melanie
YR 2017
UL http://erj.ersjournals.com/content/50/2/1602367.abstract
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.Alveolar epithelial cell senescence occurs in IPF and senolytic treatment attenuates experimental lung fibrosis http://ow.ly/nFlz30bsmNm