Eosinophils play a major role in asthma. One described mechanism leading to impaired clearance of eosinophils from the lungs is the delay in their programmed cell death (apoptosis). Phosphodiesterase 4 (PDE4) hydrolyses cyclic adenosine monophosphates (cAMP) and inhibition of its activity leads to an increase in the concentration of cAMP. Specific inhibitors of PDE4 are under development for the treatment of lung diseases because of their anti-inflammatory and bronchodilatory actions. The aim of the present study was to find out whether inhibitors of PDE4 modulate human eosinophil apoptosis.
Inhibitors of PDE3 and PDE4 (cilostazol and rolipram) inhibited spontaneous apoptosis of isolated peripheral eosinophils during in vitro culture maximally by 15 - 25%. Cell-permeable analogues of cAMP (dibutyryl-cAMP and 8-Br-cAMP) also inhibited eosinophil apoptosis in a concentration dependent manner. A beta2-agonist salbutamol delayed eosinophil apoptosis. Rolipram and cilostazol potentiated the antiapoptotic effect of salbutamol. However, PDE-inhibitors did not affect GM-CSF-induced survival of eosinophils.
The present results show that selective inhibitors of PDE3 and PDE4 delay eosinophil apoptosis and thus increase their survival in vitro. The results suggest that their effects may be mediated via an increase in intracellular cAMP concentration. Furthermore, inhibition of PDE3/4 during beta2-selective adrenergic activation may amplify beta2-agonist-induced delay in eosinophil apoptosis and this combination of drugs may worsen the eosinophilic inflammation in asthma.