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Linking airways inflammation and remodelling
S34 Effects of the cyclin-dependent kinase inhibitor R-roscovitine on eosinophil survival and clearance
  1. N Farahi1,
  2. L Uller2,
  3. J K Juss1,
  4. A J Langton1,
  5. A S Cowburn1,
  6. A Gibson3,
  7. M R Foster3,
  8. S N Farrow3,
  9. A Sobolewski1,
  10. A M Condliffe1,
  11. E R Chilvers1
  1. 1University of Cambridge, Cambridge, UK
  2. 2University of Lund, Lund, Sweden
  3. 3GlaxoSmithKline, Stevenage, UK

Abstract

Background Eosinophils are pro-inflammatory cells implicated in the pathogenesis of asthma and atopy. Apoptosis has been proposed as a potential mechanism underlying the resolution of eosinophilic inflammation and studies have indicated the ability of interventions that induce human eosinophil apoptosis to promote the resolution of eosinophilic inflammation. Recently, the cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown to enhance neutrophil apoptosis and promote the resolution of neutrophilic inflammation.

Aim The purpose of this study was to examine the expression of CDKs in human blood eosinophils, the effects of R-roscovitine on eosinophil survival and phagocytosis in vitro and determine whether R-roscovitine could influence eosinophilic lung inflammation in vivo.

Methods Eosinophils were isolated from human peripheral blood and the effects of R-roscovitine on apoptosis, degranulation and phagocytic uptake examined in vitro. The effects of R-roscovitine on eosinophilic lung inflammation in vivo were also assessed using an ovalbumin mouse model.

Results Our data demonstrate that human eosinophils express five targets for R-roscovitine: CDK1, −2, −5, −7 and −9. R-roscovitine induced eosinophil apoptosis in a time- and concentration-dependent manner but also accelerated transition to secondary necrosis as assessed by light and electron microscopy, flow cytometry and caspase activation. In addition, we report that the pro-apoptotic effect of R-roscovitine is associated with suppression of Mcl-1L expression and that the apoptotic eosinophils are phagocytosed by human monocyte derived macrophages. R-roscovitine also induced apoptosis in mouse eosinophils purified from the bone-marrow, spleen and peripheral blood. Despite this, R-roscovitine did not modulate the tissue and lumen eosinophilia characteristic of the ovalbumin mouse model of airway eosinophilia.

Conclusions These data demonstrate that R-roscovitine is capable of inducing rapid apoptosis and secondary necrosis in human eosinophils but does not affect the onset or resolution of eosinophilic airway inflammation in vivo.

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