β2-Agonists Potentiate Corticosteroid-Induced Neutrophil Survival

Neutrophils are considered to play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and severe asthma. Recent guidelines recommend the use of a combination of inhaled corticosteroids (ICS) and long-acting beta(2)-agonists (LABA) in the treatment of COPD with exacerbations and asthma not adequately controlled by ICS alone. LABA have been proposed to have a synergistic effect with corticosteroids by activating glucocorticoid receptors. The aim of this study was to investigate the effect of beta(2)-agonists on the inhibitory effects of corticosteroids on human neutrophil apoptosis. In addition, the effects of beta(2)-agonists on spontaneous neutrophil apoptosis and on GM-CSF- and LTB4-afforded survival were also evaluated. Neutrophils were isolated from human blood under sterile conditions and cultured for 16 hours. Apoptosis was assessed by relative DNA fragmentation assay. Morphological analysis was used as a control method to confirm the occurrence of apoptosis. Salbutamol, formoterol and salmeterol prolonged the lifespan of budesonide- and fluticasone propionate-treated neutrophils by inhibiting apoptosis. Formoterol and salbutamol partly reversed the inhibitory effect of GM-CSF on neutrophil apoptosis. In contrast, the effects of beta(2)-agonists on spontaneous neutrophil apoptosis and on LTB4-afforded survival were negligible. beta(2)-agonists potentiate corticosteroid-induced neutrophil survival at clinically relevant drug concentrations. Whether these effects translate into clinically relevant changes in lung neutrophil numbers remains to be demonstrated.