Germain N, Bertin B, Legendre A, Martin B, Lagente V, Payne A, Boichot E
INSERM U456, Laboratoire de Pharmacodynamie et de Pharmacologie Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, France.
Eur Respir J. 1998 Dec;12(6):1334-9. doi: 10.1183/09031936.98.12061334.
The aim of this study was to investigate the effects of selective phosphodiesterase (PDE)3 and PDE4 inhibitors on arachidonate release by alveolar macrophages from sensitized and challenged guinea-pigs. Guinea-pigs were sensitized and challenged with ovalbumin administered by aerosol. Bronchoalveolar lavage was performed 48 h later and the PDE and cyclic adenosine monophosphate (cAMP) contents of or the arachidonate release from alveolar macrophages, stimulated in vitro with N-formyl-Met-Leu-Phe (fMLP), were evaluated. PDE3 and PDE4 activities were detected in preparations of macrophage lysate from sensitized challenged and sensitized control animals. Oral pretreatment, prior to antigen challenge in sensitized guinea-pigs, with rolipram or Ro 20-1724 (PDE4 inhibitors) but not milrinone (PDE3 inhibitor) significantly reduced the arachidonate release from alveolar macrophages. In vitro incubation of alveolar macrophages from challenged guinea-pigs with Ro 20-1724 or the cAMP analogue dibutyryl cAMP (db-cAMP) but not milrinone or the cyclic guanosine monophosphate (cGMP) analogue 8-bromo-cGMP (8-br-cGMP) significantly reduced arachidonate release. Incubation of the cells with a combination of milrinone plus rolipram or Ro 20-1724 elicited a marked and significant reduction in arachidonate release by alveolar macrophages stimulated with fMLP. In conclusion, these data show that phosphodiesterase-4 isoenzyme may regulate the release of inflammatory mediators such as arachidonate from macrophages through an increase in intracellular cyclic adenosine monophosphate. This suggests that phosphodiesterase-4 inhibitors have potential in the treatment of inflammatory disorders of the lung.
本研究旨在探讨选择性磷酸二酯酶（PDE）3和PDE4抑制剂对致敏和激发豚鼠肺泡巨噬细胞花生四烯酸释放的影响。豚鼠经雾化给予卵清蛋白致敏和激发。48小时后进行支气管肺泡灌洗，并评估体外经N-甲酰甲硫氨酰亮氨酰苯丙氨酸（fMLP）刺激的肺泡巨噬细胞的PDE和环磷酸腺苷（cAMP）含量或花生四烯酸释放情况。在致敏激发动物和致敏对照动物的巨噬细胞裂解物制剂中检测到PDE3和PDE4活性。在致敏豚鼠抗原激发前口服预处理咯利普兰或Ro 20-1724（PDE4抑制剂），而非米力农（PDE3抑制剂），可显著降低肺泡巨噬细胞的花生四烯酸释放。用Ro 20-1724或cAMP类似物二丁酰cAMP（db-cAMP）而非米力农或环磷酸鸟苷（cGMP）类似物8-溴-cGMP（8-br-cGMP）对激发豚鼠的肺泡巨噬细胞进行体外孵育，可显著降低花生四烯酸释放。用米力农加咯利普兰或Ro 20-1724组合孵育细胞，可使fMLP刺激的肺泡巨噬细胞的花生四烯酸释放显著降低。总之，这些数据表明磷酸二酯酶-4同工酶可能通过增加细胞内环磷酸腺苷来调节巨噬细胞中花生四烯酸等炎症介质的释放。这表明磷酸二酯酶-4抑制剂在治疗肺部炎症性疾病方面具有潜力。
