Cyclodextrins reduce the ability of Pseudomonas aeruginosa outer-membrane vesicles to reduce CFTR Cl- secretion
Cyclodextrins reduce the ability of Pseudomonas aeruginosa outer-membrane vesicles to reduce CFTR Cl- secretion
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DOI：
10.1152/ajplung.00316.2018
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发表时间：
2019-01-01
影响因子：
4.9
通讯作者：
Stanton, Bruce A.
中科院分区：
文献类型：
--
作者：
Barnaby, Roxanna;Koeppen, Katja;Stanton, Bruce A.
铜绿假单胞菌分泌外膜囊泡（OMV），其与气道上皮细胞顶膜中富含胆固醇的脂筏融合，并降低wt-CFTR Cl-分泌。在此，我们测试了以下假设：通过环糊精降低CF人气道上皮细胞的胆固醇含量降低了OMV对VX-809（鲁玛卡托）刺激的Phe 508 del CFTR Cl-分泌的抑制作用。用媒介物、羟丙基-β-环糊精（HP β CD）或甲基-β-环糊精（M β CD）处理原代CF支气管上皮细胞和CFBE细胞，并在Ussing室中测量铜绿假单胞菌分泌的OMV对VX-809刺激的Phe 508 del CFTR Cl-分泌的影响。HP β CD和M β CD都没有细胞毒性，也都没有改变Phe 508 del CFTR Cl-分泌。当添加到CF单层的顶侧时，两种环糊精都降低了VX-809刺激的Phe 508 del-CFTR Cl-分泌的OMV抑制。两种环糊精还降低了铜绿假单胞菌形成生物膜的能力，并抑制了铜绿假单胞菌的生长。我们的数据表明，HP β CD（正在进行C型尼曼-匹克病的临床试验）和M β CD（已被美国食品和药物管理局批准用于溶解亲脂性药物）在添加到气道上皮细胞的顶侧时可增强VX-809在CF患者中的临床疗效，并减少铜绿假单胞菌的促生长和生物膜形成。这两种效果对CF患者都是有益的。
Pseudomonas aeruginosa secretes outer-membrane vesicles (OMVs) that fuse with cholesterol-rich lipid rafts in the apical membrane of airway epithelial cells and decrease wt-CFTR Cl- secretion. Herein, we tested the hypothesis that a reduction of the cholesterol content of CF human airway epithelial cells by cyclodextrins reduces the inhibitory effect of OMVs on VX-809 (lumacaftor)-stimulated Phe508del CFTR Cl- secretion. Primary CF bronchial epithelial cells and CFBE cells were treated with vehicle, hydroxypropyl-beta-cyclodextrin (HP beta CD), or methyl-beta-cyclodextrin (M beta CD), and the effects of OMVs secreted by P. aeruginosa on VX-809 stimulated Phe508del CFTR Cl- secretion were measured in Ussing chambers. Neither HP beta CD nor M beta CD were cytotoxic, and neither altered Phe508del CFTR Cl- secretion. Both cyclodextrins reduced OMV inhibition of VX-809-stimulated Phe508del-CFTR Cl- secretion when added to the apical side of CF monolayers. Both cyclodextrins also reduced the ability of P. aeruginosa to form biofilms and suppressed planktonic growth of P. aeruginosa. Our data suggest that HP beta CD, which is in clinical trials for Niemann-Pick Type C disease, and M beta CD, which has been approved by the U.S. Food and Drug Administration for use in solubilizing lipophilic drugs, may enhance the clinical efficacy of VX-809 in CF patients when added to the apical side of airway epithelial cells, and reduce planktonic growth and biofilm formation by P. aeruginosa. Both effects would be beneficial to CF patients.