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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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 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.

Detaljer

Författare
  • Mareike Lehmann
  • Martina Korfei
  • Kathrin Mutze
  • Stephan Klee
  • Wioletta Skronska-Wasek
  • Hani N. Alsafadi
  • Chiharu Ota
  • Ana Rita Costa
  • Herbert B Schiller
  • Michael Lindner
  • Darcy E Wagner
  • Andreas Günther
  • Melanie Königshoff
Externa organisationer
  • Ludwig-Maximilian University of Munich
  • University of Colorado
  • University Hospital Giessen and Marburg
Forskningsområden

Nyckelord

Originalspråkengelska
Artikelnummer1602367
Sidor (från-till)1-15
TidskriftEuropean Respiratory Journal
Volym50
StatusPublished - 2017 aug
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa