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Novel Therapy of Bicarbonate, Glutathione, and Ascorbic Acid Improves Cystic Fibrosis Mucus Transport.
American Journal of Respiratory Cell and Molecular Biology ( IF 5.9 ) Pub Date : 2020-09-01 , DOI: 10.1165/rcmb.2019-0287oc
Adegboyega Timothy Adewale 1 , Emily Falk Libby 1 , Lianwu Fu 2, 3 , Andrew Lenzie 1 , Evan R Boitet 1 , Susan E Birket 4 , Courtney Fernandez Petty 1 , J Dixon Johns 1 , Marina Mazur 1 , Guillermo J Tearney 5, 6, 7, 8 , Dan Copeland 9 , Carolyn Durham 9 , Steven M Rowe 1, 2, 3, 4
Affiliation  

Defective airway mucus clearance is a defining characteristic of cystic fibrosis lung disease, and improvements to current mucolytic strategies are needed. Novel approaches targeting a range of contributing mechanisms are in various stages of preclinical and clinical development. ARINA-1 is a new nebulized product comprised of ascorbic acid, glutathione, and bicarbonate. Using microoptical coherence tomography, we tested the effect of ARINA-1 on central features of mucociliary clearance in F508del/F508del primary human bronchial epithelial cells to assess its potential as a mucoactive therapy in cystic fibrosis. We found that ARINA-1 significantly augmented mucociliary transport rates, both alone and with CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapy, whereas airway hydration and ciliary beating were largely unchanged compared with PBS vehicle control. Analysis of mucus reflectivity and particle-tracking microrheology indicated that ARINA-1 restores mucus clearance by principally reducing mucus layer viscosity. The combination of bicarbonate and glutathione elicited increases in mucociliary transport rate comparable to those seen with ARINA-1, indicating the importance of this interaction to the impact of ARINA-1 on mucus transport; this effect was not recapitulated with bicarbonate alone or bicarbonate combined with ascorbic acid. Assessment of CFTR chloride transport revealed an increase in CFTR-mediated chloride secretion in response to ARINA-1 in CFBE41o cells expressing wild-type CFTR, driven by CFTR activity stimulation by ascorbate. This response was absent in CFBE41o F508del cells treated with VX-809 and primary human bronchial epithelial cells, implicating CFTR-independent mechanisms for the effect of ARINA-1 on cystic fibrosis mucus. Together, these studies indicate that ARINA-1 is a novel potential therapy for the treatment of impaired mucus clearance in cystic fibrosis.



中文翻译:

碳酸氢盐、谷胱甘肽和抗坏血酸的新疗法可改善囊性纤维化粘液运输。

气道粘液清除缺陷是囊性纤维化肺病的一个定义特征,需要改进当前的粘液溶解策略。针对一系列贡献机制的新方法处于临床前和临床开发的不同阶段。ARINA-1 是一种新的雾化产品,由抗坏血酸、谷胱甘肽和碳酸氢盐组成。使用显微光学相干断层扫描,我们测试了 ARINA-1 对 F508del/F508del 原代人支气管上皮细胞黏液纤毛清除中心特征的影响,以评估其作为囊性纤维化黏液活性疗法的潜力。我们发现 ARINA-1 显着增加了黏液纤毛转运率,无论是单独使用还是与 CFTR(囊性纤维化跨膜电导调节剂)调节剂治疗,而气道水合作用和纤毛搏动与 PBS 载体对照相比基本没有变化。粘液反射率和粒子追踪微流变学分析表明,ARINA-1 主要通过降低粘液层粘度来恢复粘液清除。碳酸氢盐和谷胱甘肽的组合引起粘液纤毛运输速率的增加,与 ARINA-1 相当,表明这种相互作用对 ARINA-1 对粘液运输的影响的重要性;单独使用碳酸氢盐或与抗坏血酸结合使用碳酸氢盐不能重现这种效果。CFTR 氯离子转运的评估显示 CFTR 介导的氯离子分泌增加,以响应 CFBE41o 中的 ARINA-1 粘液反射率和粒子追踪微流变学分析表明,ARINA-1 主要通过降低粘液层粘度来恢复粘液清除。碳酸氢盐和谷胱甘肽的组合引起粘液纤毛运输速率的增加,与 ARINA-1 相当,表明这种相互作用对 ARINA-1 对粘液运输的影响的重要性;单独使用碳酸氢盐或与抗坏血酸结合使用碳酸氢盐不能重现这种效果。CFTR 氯离子转运的评估显示 CFTR 介导的氯离子分泌增加,以响应 CFBE41o 中的 ARINA-1 粘液反射率和粒子追踪微流变学分析表明,ARINA-1 主要通过降低粘液层粘度来恢复粘液清除。碳酸氢盐和谷胱甘肽的组合引起粘液纤毛运输速率的增加,与 ARINA-1 相当,表明这种相互作用对 ARINA-1 对粘液运输的影响的重要性;单独使用碳酸氢盐或与抗坏血酸结合使用碳酸氢盐不能重现这种效果。CFTR 氯离子转运的评估显示 CFTR 介导的氯离子分泌增加,以响应 CFBE41o 中的 ARINA-1 表明这种相互作用对 ARINA-1 对粘液运输的影响的重要性;单独使用碳酸氢盐或与抗坏血酸结合使用碳酸氢盐不能重现这种效果。CFTR 氯离子转运的评估显示 CFTR 介导的氯离子分泌增加,以响应 CFBE41o 中的 ARINA-1 表明这种相互作用对 ARINA-1 对粘液运输的影响的重要性;单独使用碳酸氢盐或与抗坏血酸结合使用碳酸氢盐不能重现这种效果。CFTR 氯离子转运的评估显示 CFTR 介导的氯离子分泌增加,以响应 CFBE41o 中的 ARINA-1-表达野生型 CFTR 的细胞,由抗坏血酸的 CFTR 活性刺激驱动。这种反应在用 VX-809 处理的CFBE41o - F508del 细胞和原代人支气管上皮细胞中不存在,这表明 ARINA-1 对囊性纤维化粘液的影响存在 CFTR 非依赖性机制。总之,这些研究表明 ARINA-1 是治疗囊性纤维化粘液清除受损的新型潜在疗法。

更新日期:2020-09-01
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