Poschet Jens F, Fazio Joseph A, Timmins Graham S, Ornatowski Wojciech, Perkett Elizabeth, Delgado Monica, Deretic Vojo
Department of Molecular Genetics & Microbiology, School of Medicine, University of New Mexico, Albuquerque, New Mexico, 87131, USA.
EMBO Rep. 2006 May;7(5):553-9. doi: 10.1038/sj.embor.7400674. Epub 2006 Apr 13.
Endosomal hyperacidification in cystic fibrosis (CF) respiratory epithelial cells is secondary to a loss of sodium transport control owing to a defective form of the CF transmembrane conductance regulator CFTR. Here, we show that endosomal hyperacidification can be corrected by activating the signalling cascade controlling sodium channels through cyclic GMP. Nitric oxide (NO) donors corrected the endosomal hyperacidification in CF cells. Stimulation of CF cells with guanylate cyclase agonists corrected the pH in endosomes. Exposure of CF cells to an inhibitor of cGMP-specific phosphodiesterase PDE5, Sildenafil, normalized the endosomal pH. Treatment with Sildenafil reduced secretion by CF cells of the proinflammatory chemokine interleukin 8 following stimulation with Pseudomonas aeruginosa products. Thus, the endosomal hyperacidification and excessive proinflammatory response in CF are in part due to deficiencies in NO- and cGMP-regulated processes and can be pharmacologically reversed using PDE5 inhibitors.
囊性纤维化（CF）呼吸道上皮细胞中的内体过度酸化是由于CF跨膜电导调节因子CFTR的缺陷形式导致钠转运控制丧失的继发结果。在此，我们表明通过环鸟苷酸激活控制钠通道的信号级联反应可以纠正内体过度酸化。一氧化氮（NO）供体纠正了CF细胞中的内体过度酸化。用鸟苷酸环化酶激动剂刺激CF细胞可纠正内体的pH值。将CF细胞暴露于cGMP特异性磷酸二酯酶PDE5的抑制剂西地那非后，内体pH值恢复正常。用西地那非治疗可减少铜绿假单胞菌产物刺激后CF细胞促炎趋化因子白细胞介素8的分泌。因此，CF中的内体过度酸化和过度促炎反应部分归因于NO和cGMP调节过程的缺陷，并且可以使用PDE5抑制剂进行药理学逆转。
