Science and Research

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

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 beta-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.

  • Lehmann, M.
  • Korfei, M.
  • Mutze, K.
  • Klee, S.
  • Skronska-Wasek, W.
  • Alsafadi, H. N.
  • Ota, C.
  • Costa, R.
  • Schiller, H. B.
  • Lindner, M.
  • Wagner, D. E.
  • Gunther, A.
  • Konigshoff, M.

Keywords

  • Alveolar Epithelial Cells/*drug effects
  • Animals
  • Biomarkers/*metabolism
  • *Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p16/genetics/metabolism
  • Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism
  • Humans
  • Idiopathic Pulmonary Fibrosis/*metabolism/pathology
  • Lung/pathology
  • Mice
Publication details
DOI: 10.1183/13993003.02367-2016
Journal: Eur Respir J
Number: 2
Work Type: Original
Location: CPC-M, UGMLC
Disease Area: DPLD
Partner / Member: ASK, HMGU, KUM
Access-Number: 28775044
See publication on PubMed

DZL Engagements

chevron-down