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

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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
External organisations
  • Ludwig-Maximilian University of Munich
  • University of Colorado
  • University Hospital Giessen and Marburg
Research areas and keywords

Keywords

  • Journal Article
Original languageEnglish
Article number1602367
Pages (from-to)1-15
JournalEuropean Respiratory Journal
Volume50
Publication statusPublished - 2017 Aug
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes