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首页> 外文期刊>American Journal of Physiology >Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis.
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Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis.

机译：磷酸二酯酶5抑制剂对cGMP水平的药理调节，作为治疗囊性纤维化呼吸道疾病的治疗策略。

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摘要

The CFTR gene encodes a chloride channel with pleiotropic effects on cell physiology and metabolism. Here, we show that increasing cGMP levels to inhibit epithelial Na(+) channel in cystic fibrosis (CF) respiratory epithelial cells corrects several aspects of the downstream pathology in CF. Cell culture models, using a range of CF cell lines and primary cells, showed that complementary pharmacological approaches to increasing intracellular cGMP, by elevating guanyl cyclase activity though reduced nitric oxide, addition of cell-permeable cGMP analogs, or inhibition of phosphodiesterase 5 corrected multiple aspects of the CF pathological cascade. These included correction of defective protein glycosylation, bacterial adherence, and proinflammatory responses. Furthermore, pharmacological inhibition of phosphodiesterase 5 in tissues ex vivo or in animal models improved transepithelial currents across nasal mucosae from transgenic F508del Cftr(tm1Eur) mice and reduced neutrophil infiltration on bacterial aerosol challenge in Pseudomonas aeruginosa-susceptible DBA/2 mice. Our findings define phosphodiesterase 5 as a specific target for correcting a number of previously disconnected defects in the CF respiratory tract, now linked through this study. Our study suggests that phosphodiesterase 5 inhibition provides an opportunity for simultaneous and concerted correction of seemingly disparate complications in CF.
机译：CFTR基因编码对细胞生理和代谢具有多效性的氯离子通道。在这里，我们显示增加cGMP水平以抑制囊性纤维化（CF）呼吸道上皮细胞中的上皮Na（+）通道可纠正CF中下游病理的几个方面。使用一系列CF细胞系和原代细胞的细胞培养模型表明，通过降低氧化氮，提高鸟苷酸环化酶活性，添加可渗透细胞的cGMP类似物或抑制磷酸二酯酶5来提高细胞内cGMP的互补药理学方法纠正了多种CF病理级联的各个方面。这些措施包括纠正有缺陷的蛋白质糖基化，细菌粘附和促炎反应。此外，离体或动物模型中组织中磷酸二酯酶5的药理抑制作用改善了转基因F508del Cftr（tm1Eur）小鼠鼻粘膜的跨上皮电流，并减少了铜绿假单胞菌易感性DBA / 2小鼠对细菌气溶胶攻击的中性粒细胞浸润。我们的发现将磷酸二酯酶5定义为纠正CF呼吸道中许多先前断开连接的缺陷的特定靶标，现在已通过这项研究进行了关联。我们的研究表明，磷酸二酯酶5的抑制作用为同时且协同纠正CF中看似完全不同的并发症提供了机会。

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