title: The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome.
abstract: 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.
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: David A
authors.identifier: 0000-0002-4658-8829
authors.initials: DA
authors.lastname: Dorward
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Felton
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Calum T
authors.initials: CT
authors.lastname: Robb
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Craven
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Tiina
authors.initials: T
authors.lastname: Kipari
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.|Department of Critical Care, Anaesthesia and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Walsh
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Haslett
authors.affiliation: Department of Critical Care, Anaesthesia and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK.
authors.forename: Kallirroi
authors.initials: K
authors.lastname: Kefala
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Adriano G
authors.initials: AG
authors.lastname: Rossi
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Lucas
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects*; D010880:Piperidines / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000209:etiology*; D018805:Sepsis / Q000150:complications*; D015996:Survival Rate
chemical_list: C531230:4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide; D015415:Biomarkers; D016207:Cytokines; D010880:Piperidines; D011720:Pyrazoles
keywords: ARDS; Innate Immunity; Neutrophil Biology