Faisy Christophe, Risse Paul-André, Naline Emmanuel, Guerot Emmanuel, Fagon Jean-Yves, Devillier Phillipe, Advenier Charles
UPRES EA220, Faculté de Médecine Paris-Ouest and UFR Biomédicale des Saints-Pères, 45 rue des Saints-Pères, 75006 Paris, France.
Life Sci. 2006 Oct 12;79(20):1929-35. doi: 10.1016/j.lfs.2006.06.020. Epub 2006 Jun 20.
Chronic exposure of human isolated bronchi to beta2-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 beta2-adrenoceptor stimulation provokes bronchial hyperresponsiveness. Samples from eighteen human bronchi were sensitized to ET-1 by prolonged incubation with 0.1 microM fenoterol (15 h, 21 degrees C), or, under similar conditions, were incubated with a selective type-3 phosphodiesterase inhibitor (1 microM siguazodan), two selective type-4 phosphodiesterase inhibitors (0.1 microM rolipram and 0.1 microM cilomilast), a combination of fenoterol and rolipram (0.1 microM each) or of fenoterol and cilomilast (0.1 microM 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 beta2-adrenergic agonists.
人离体支气管长期暴露于β2-肾上腺素能激动剂，尤其是非诺特罗，会增强其对内皮素-1（ET-1）的平滑肌收缩反应，ET-1是一种与慢性炎症性气道疾病有关的肽。5'-环磷酸腺苷（cAMP）通路参与了非诺特罗诱导的高反应性。本研究调查了通过β2-肾上腺素能受体刺激以外的其他途径使细胞内cAMP长期升高是否会引发支气管高反应性。将来自18条人支气管的样本与0.1微摩尔非诺特罗（15小时，21摄氏度）长时间孵育，使其对ET-1敏感，或者在类似条件下，与一种选择性3型磷酸二酯酶抑制剂（1微摩尔西加唑旦）、两种选择性4型磷酸二酯酶抑制剂（0.1微摩尔咯利普兰和0.1微摩尔西洛司特）、非诺特罗与咯利普兰的组合（各0.1微摩尔）或非诺特罗与西洛司特的组合（各0.1微摩尔）孵育。咯利普兰和西洛司特而非西加唑旦诱导了高反应性（分别与配对对照组相比，p < 0.01和p < 0.05），类似于非诺特罗的作用。与西洛司特共同孵育可显著增强非诺特罗诱导的支气管高反应性（与单独使用非诺特罗相比，p < 0.05），但与咯利普兰共同孵育则无此作用。我们的结果表明，通过抑制磷酸二酯酶4使细胞内cAMP长期激活会诱导人离体支气管对ET-1产生高反应性。然而，当人支气管持续暴露于有或无β2-肾上腺素能激动剂的选择性磷酸二酯酶抑制剂时，磷酸二酯酶4亚细胞定位的差异可能会引发不同的反应模式。
