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. 2017 Feb;72(2):182-185.
doi: 10.1136/thoraxjnl-2016-209229. Epub 2016 Oct 24.

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

David A Dorward  1 , Jennifer M Felton  1 , Calum T Robb  1 , Thomas Craven  1 , Tiina Kipari  1 , Timothy S Walsh  1   2 , Christopher Haslett  1 , Kallirroi Kefala  2 , Adriano G Rossi  1 , Christopher D Lucas  1
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V体育平台登录 - The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome

David A Dorward et al. Thorax. 2017 Feb.

"VSports手机版" 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 VSports手机版. 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. .

Keywords: ARDS; Innate Immunity; Neutrophil Biology. V体育安卓版.

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Conflict of interest statement

Conflicts of Interest: None declared.

Figures

Figure 1
Figure 1
Neutrophils isolated from patients with acute respiratory distress syndrome (ARDS) exhibit an intrinsic delay in spontaneous apoptosis. Blood neutrophils from patients with ARDS and healthy volunteers were cultured for 0, 6, 13 and 20 hours with cell viability (AnnV−ve/PI−ve), apoptosis (AnnV+ve/PI−ve) and necrosis (PI+ve) assessed by flow cytometry. (A) Cell viability over the time period; (B) representative flow cytometry plots and cytocentrifuge preparations at 0 and 20 hours (400× magnification); (C) the proportion of viable, apoptotic and neutrophils following 13 hours culture; circulating interleukin (IL)-8 (D), IL-6 (E) and C reactive protein (CRP) (F) levels in plasma; (G) cell viability of both healthy control and ARDS neutrophils at 20 hours following incubation with autologous (Auto) or fetal calf serum (FCS); (H) cleaved caspase 3 expression following 4 hours culture quantified by densitometry (I), (J) Mcl-1 expression in freshly isolated neutrophils are shown. (A) ***p<0.001 repeated measures analysis of variance with Sidak's multiple comparisons test, (D)–(G) and (I) Mann-Whitney U test ((A) (C) and (G)) n=5/group; (D)–(F) n=3 healthy, n=5 ARDS; (H)–(J) n=4 healthy, n=5 ARDS)).
Figure 2
Figure 2
AT7519 induces time-dependent neutrophil apoptosis in acute respiratory distress syndrome (ARDS) with associated loss of Mcl-1 expression. Neutrophils were cultured in the presence or absence of the cyclin-dependent kinase inhibitor AT7519 (AT; 1 μM) for 0, 6, 13 and 20 hours with subsequent flow cytometry analysis. (A) Cell viability over the time period, (B) representative flow cytometry plots and cytocentrifuge preparations at 20 hours from ARDS neutrophils (400× magnification); (C) apoptosis of ARDS neutrophils following treatment with AT7519 over the time period; (D) representative paired Mcl-1 expression after 4 hours treatment with or without AT7519 (n=2) with cumulative densitometry (n=5) (E) shown. (A) and (C) *p<0.05, ***p<0.001 repeated measures analysis of variance with Sidak's multiple comparisons test; (A) *comparison between healthy volunteer neutrophil treatment groups, #comparison between ARDS neutrophils; (E) Wilcoxon matched-pairs signed-rank test; n=5/group all experiments.
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References

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