{
  "abstract": "Background Cellular senescence contributes to accelerated lung ageing observed in COPD. It is characterised by the cessation of cell division, upregulation of cell cycle inhibitors, p21 CIP1 and p16INK4a and the downregulation of anti-ageing molecule sirtuin (SIRT).1 Extracellular vesicles (EVs) derived from COPD small airway epithelial cells induce cellular senescence in healthy epithelial cells. This study investigated whether SAF-derived EVs from COPD patients induce senescence in a bronchial epithelial cell line and whether inhibiting EV uptake can attenuate this.Methods EVs were isolated from non-smoker or COPD SAFs and fluorescently labelled with pkh67. Bronchial epithelial cell line BEAS-2B cells were exposed to PKH67-labelled EVs, and EV uptake was quantified by flow cytometry. Senescence-associated gene expression (p16 INK4a, p21CIP1, SIRT1) was measured by qRT-PCR. To examine uptake mechanisms, cells were treated with Dynasore (dynamin inhibitor) or Pitstop (clathrin inhibitor) prior to EV exposure.Results SAF-derived EVs were internalised by BEAS-2B cells in a time-dependent manner, with higher uptake for non-smokers than COPD-derived EVs by approximately 10% for small EVs and 20% for large EVs. COPD-derived EVs induced elevated expression of p16 INK4a by 1.2-fold (n=5; p < 0.05) and p21CIP1 by 2-fold (n=5; p < 0.05) and downregulation of SIRT1 expression from baseline to 0.8 (n=4; p < 0.05). Dynasore, but not Pitstop, significantly reduced EV uptake which leads to the inhibition of p21CIP1 (n=5; p < 0.05) and p16INK4a (n=5; p < 0.01) expression induced by COPD EVs.Discussion COPD SAF-derived EVs promote epithelial senescence via dynamin-mediated endocytosis, implicating EVs in fibroblast-epithelial signalling in COPD. The findings are consistent with previous studies demonstrating that EVs from diseased cells can transfer pro-senescent signals to recipient epithelial cells. Blocking EV uptake effectively attenuated this senescent response, suggesting a potential therapeutic strategy to disrupt fibroblast-driven airway remodelling. Further studies are warranted to validate findings in primary epithelial cells.References Devulder JV, Baker JR, Fenwick PS, Odqvist L, Donnelly LE, Barnes PJ. PMID: 39836066Wrench CL, Baker JR, Monkley S, Fenwick PS, Murray L, Donnelly LE, Barnes PJ. PMID: 38150543",
  "authors": [
    {
      "affiliations": [
        "Imperial College London, London, UK"
      ],
      "name": "NK Tzionis"
    },
    {
      "affiliations": [
        "Imperial College London, London, UK"
      ],
      "name": "JV Devulder"
    },
    {
      "affiliations": [
        "Imperial College London, London, UK"
      ],
      "name": "PS Fenwick"
    },
    {
      "affiliations": [
        "Imperial College London, London, UK"
      ],
      "name": "PJ Barnes"
    },
    {
      "affiliations": [
        "Imperial College London, London, UK"
      ],
      "name": "LE Donnelly"
    }
  ],
  "title": "S120 The role of fibroblast-derived extracellular vesicles in epithelial cell senescence in COPD",
  "uid": "6170b7cd-e9cb-5049-afcb-6717d6935680"
}