Phosphodiesterase 4 inhibitors modulate beta(2)-adrenoceptor agonist-induced human airway hyperresponsiveness

摘要

Chronic exposure of human isolated bronchi to beta(2)-adrenergic agonists, especially fenoterol, potentiates smooth muscle contraction in response to endothelin-1 (ET-1), a peptide implicated in chronic inflammatory airway diseases. 5'-Cyclic adenosine monophosphate (cAMP) pathways are involved in fenoterol-induced hyperresponsiveness. The present study investigated whether chronic elevation of intracellular cAMP by other pathways than beta(2)-adrenoceptor stimulation provokes bronchial hyperresponsiveness. Samples from eighteen human bronchi were sensitized to ET-I by prolonged incubation with 0.1 mu M tenoterol (15 h, 21 degrees C), or, under similar conditions, were incubated with a selective type-3 phosphodiesterase inhibitor (1 mu M siguazodan), two selective type-4 phosphodiesterase inhibitors (0.1 mu M rolipram and 0.1 mu M cilomilast), a combination of fenoterol and rolipram (0.1 mu M each) or of fenoterol and cilomilast (0.1 mu M each). Rolipram and cilomilast, but not siguazodan, induced hyperresponsiveness (p < 0.01 and p < 0.05 vs. paired controls, respectively) similar to the fenoterol effect. Fenoterol-induced bronchial hyperresponsiveness was significantly enhanced by coincubation with cilomilast (p < 0.05 vs. fenoterol alone) but not with rolipram. Our results suggest that prolonged activation of intracellular cAMP through phosphodiesterase 4 inhibition induces hyperresponsiveness to ET-1 in human isolated bronchi. However, differences in subcellular localization of phosphodiesterase 4 may provoke divergent responsiveness patterns when human bronchi are continuously exposed to selective phosphodiesterase inhibitors with or without beta(2)-adrenergic agonists. (c) 2006 Elsevier Inc. All rights reserved.