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The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome
  1. David A Dorward1,
  2. Jennifer M Felton1,
  3. Calum T Robb1,
  4. Thomas Craven1,
  5. Tiina Kipari1,
  6. Timothy S Walsh1,2,
  7. Christopher Haslett1,
  8. Kallirroi Kefala2,
  9. Adriano G Rossi1,
  10. Christopher D Lucas1
  1. 1 The MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
  2. 2 Department of Critical Care, Anaesthesia and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
  1. Correspondence to Dr David A Dorward, The MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK; david.dorward{at}


Acute respiratory distress syndrome (ARDS) is a neutrophil-dominant disorder with no effective pharmacological therapies. While the cyclin-dependent kinase inhibitor AT7519 induces neutrophil apoptosis to promote inflammation resolution in preclinical models of lung inflammation, its potential efficacy in ARDS has not been examined. Untreated peripheral blood sepsis-related ARDS neutrophils demonstrated prolonged survival after 20 hours in vitro culture. AT7519 was able to override this phenotype to induce apoptosis in ARDS neutrophils with reduced expression of the pro-survival protein Mcl-1. We demonstrate the first pharmacological compound to induce neutrophil apoptosis in sepsis-related ARDS, highlighting cyclin-dependent kinase inhibitors as potential novel therapeutic agents.

  • Neutrophil Biology
  • ARDS
  • Innate Immunity

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  • AGR and CDL joint senior authors

  • Contributors DAD, TC and KK obtained clinical samples. DAD, CDL, JMF, TC, CTR and TK performed experiments. DAD, CDL, CH, TW and AGR designed experiments. DAD, CDL and AGR analysed data and wrote the manuscript.

  • Funding The authors acknowledge funding from the Wellcome Trust WT096497 (DAD) and WT094415 (CDL), UK Medical Research Council (MR/K013386/1: AGR, CTR, TK and JMF).

  • Competing interests None declared.

  • Ethics approval Lothian Research Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.