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
- 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.