The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome

David A Dorward; Jennifer M Felton; Calum T Robb; Thomas Craven; Tiina Kipari; Timothy S Walsh; Christopher Haslett; Kallirroi Kefala; Adriano G Rossi; Christopher D Lucas

doi:10.1136/thoraxjnl-2016-209229

The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome

David A Dorward, Jennifer M Felton, Calum T Robb, Thomas Craven, Tiina Kipari, Timothy S Walsh, Christopher Haslett, Kallirroi Kefala, Adriano G Rossi, Christopher D Lucas

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Pages (from-to)	182-185
Number of pages	4
Journal	Thorax
Volume	72
Issue number	2
Early online date	24 Oct 2016
DOIs	https://doi.org/10.1136/thoraxjnl-2016-209229
Publication status	Published - Feb 2017

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10.1136/thoraxjnl-2016-209229Licence: Creative Commons: Attribution (CC-BY)

The role of cyclin-dependent kinase-9 inhibition in promoting the resolution of chronic inflammation
Rossi, A. & Haslett, C.
MRC
1/05/13 → 30/10/19
Project: Research
Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative. Dr D Dorward
Webb, D.
UK-based charities
1/04/11 → 31/03/14
Project: Research
Edinburgh Clinical Academic Track (ECAT) training Programme - Dr Christopher Lucas
Rossi, A.
UK-based charities
1/08/10 → 31/07/13
Project: Research

Christopher Lucas
- Deanery of Clinical Sciences - MRC Clinician Scientist
- Centre for Inflammation Research
Person: Academic: Research Active

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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.",

author = "Dorward, {David A} and Felton, {Jennifer M} and Robb, {Calum T} and Thomas Craven and Tiina Kipari and Walsh, {Timothy S} and Christopher Haslett and Kallirroi Kefala and Rossi, {Adriano G} and Lucas, {Christopher D}",

year = "2017",

month = feb,

doi = "10.1136/thoraxjnl-2016-209229",

language = "English",

volume = "72",

pages = "182--185",

journal = "Thorax",

issn = "0040-6376",

publisher = "BMJ Publishing Group",

number = "2",

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TY - JOUR

T1 - The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome

AU - Dorward, David A

AU - Felton, Jennifer M

AU - Robb, Calum T

AU - Craven, Thomas

AU - Kipari, Tiina

AU - Walsh, Timothy S

AU - Haslett, Christopher

AU - Kefala, Kallirroi

AU - Rossi, Adriano G

AU - Lucas, Christopher D

PY - 2017/2

Y1 - 2017/2

N2 - 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.

AB - 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.

U2 - 10.1136/thoraxjnl-2016-209229

DO - 10.1136/thoraxjnl-2016-209229

M3 - Article

SN - 0040-6376

VL - 72

SP - 182

EP - 185

JO - Thorax

JF - Thorax

IS - 2

ER -

The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome

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Projects

The role of cyclin-dependent kinase-9 inhibition in promoting the resolution of chronic inflammation

Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative. Dr D Dorward

Edinburgh Clinical Academic Track (ECAT) training Programme - Dr Christopher Lucas

Profiles

Christopher Lucas

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