Document Detail


Phosphodiesterase 4 inhibitors delay human eosinophil and neutrophil apoptosis in the absence and presence of salbutamol.
MedLine Citation:
PMID:  18282775     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In asthma and chronic obstructive pulmonary disease (COPD), the number of eosinophils and neutrophils in the lung is increased. One described mechanism leading to the impaired clearance of these cells from the lung is the delay in their programmed cell death (apoptosis). Selective inhibitors of phosphodiesterases (PDEs) are under development for the treatment of lung diseases because of their anti-inflammatory and bronchodilator activity. The aim of the present study was to establish whether inhibitors of PDE3, PDE4 and PDE5 modulate human eosinophil or neutrophil apoptosis or beta 2-adrenoceptor agonist- or cytokine-afforded survival. We also evaluated whether a PDE4 inhibitor could modulate the effect of a corticosteroid on eosinophil and neutrophil apoptosis. Apoptosis was measured by using the relative DNA fragmentation assay and Annexin-V binding. Inhibitors of PDE4 (rolipram; 0.1-10 microM) and PDE3 (cilostazol; 0.1-10 microM) delayed spontaneous eosinophil apoptosis maximally by 25% and 15%, respectively. A combination of a PDE4 or PDE3 inhibitor (10 microM) with salbutamol (100 nM) further delayed eosinophil apoptosis maximally by 42-49%. In neutrophils, rolipram (10 microM) also decreased apoptosis with a maximal inhibition of 13%. The combination of rolipram (10 microM) and salbutamol (100 nM) produced a 27% inhibition of neutrophil apoptosis. Inhibitor of cGMP-specific PDE5 (zaprinast; 0.1-10 microM) did not affect eosinophil apoptosis and only slightly increased spontaneous neutrophil apoptosis. The effect of budesonide on apoptosis was not significantly modulated by a PDE4 inhibitor in eosinophils or neutrophils. The present results show that selective inhibitors of cAMP-hydrolyzing PDEs (PDE3 and PDE4) delay eosinophil apoptosis and, thus, increase their survival in vitro. Furthermore, beta 2-adrenoceptor agonists enhance the anti-apoptotic effects of PDE3 and PDE4 inhibitors, suggesting that such drug combinations may prolong eosinophil and neutrophil longevity in the lung.
Authors:
Jouni Parkkonen; Hannele Hasala; Eeva Moilanen; Mark A Giembycz; Hannu Kankaanranta
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-11-22
Journal Detail:
Title:  Pulmonary pharmacology & therapeutics     Volume:  21     ISSN:  1094-5539     ISO Abbreviation:  Pulm Pharmacol Ther     Publication Date:  2008  
Date Detail:
Created Date:  2008-05-12     Completed Date:  2008-10-27     Revised Date:  2013-05-30    
Medline Journal Info:
Nlm Unique ID:  9715279     Medline TA:  Pulm Pharmacol Ther     Country:  England    
Other Details:
Languages:  eng     Pagination:  499-506     Citation Subset:  IM    
Affiliation:
The Immunopharmacology Research Group, Medical School, University of Tampere and Research Unit, Tampere University Hospital, Tampere, Finland.
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MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-Agonists / pharmacology*
Albuterol / pharmacology*
Annexin A5 / metabolism
Anti-Inflammatory Agents / pharmacology
Apoptosis / drug effects*
Budesonide / pharmacology
Cell Survival / drug effects
DNA Fragmentation / drug effects
Eosinophils / drug effects*
Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
Humans
Neutrophils / drug effects*
Phosphodiesterase 4 Inhibitors*
Phosphodiesterase Inhibitors / pharmacology*
Purinones / pharmacology
Rolipram / pharmacology
Tetrazoles / pharmacology
Chemical
Reg. No./Substance:
0/Adrenergic beta-Agonists; 0/Annexin A5; 0/Anti-Inflammatory Agents; 0/Phosphodiesterase 4 Inhibitors; 0/Phosphodiesterase Inhibitors; 0/Purinones; 0/Tetrazoles; 18559-94-9/Albuterol; 51333-22-3/Budesonide; 61413-54-5/Rolipram; 83869-56-1/Granulocyte-Macrophage Colony-Stimulating Factor; GXT25D5DS0/zaprinast; N7Z035406B/cilostazol

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