U.O.C. Genetica Medica, Istituto Giannina Gaslini, Genova, Italy.
Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
JCI Insight. 2018 Feb 8;3(3). doi: 10.1172/jci.insight.98699.
In cystic fibrosis (CF), deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel causes misfolding and premature degradation. Considering the numerous effects of the F508del mutation on the assembly and processing of CFTR protein, combination therapy with several pharmacological correctors is likely to be required to treat CF patients. Recently, it has been reported that thymosin α-1 (Tα-1) has multiple beneficial effects that could lead to a single-molecule-based therapy for CF patients with F508del. Such effects include suppression of inflammation, improvement in F508del-CFTR maturation and gating, and stimulation of chloride secretion through the calcium-activated chloride channel (CaCC). Given the importance of such a drug, we aimed to characterize the underlying molecular mechanisms of action of Tα-1. In-depth analysis of Tα-1 effects was performed using well-established microfluorimetric, biochemical, and electrophysiological techniques on epithelial cell lines and primary bronchial epithelial cells from CF patients. The studies, which were conducted in 2 independent laboratories with identical outcome, demonstrated that Tα-1 is devoid of activity on mutant CFTR as well as on CaCC. Although Tα-1 may still be useful as an antiinflammatory agent, its ability to target defective anion transport in CF remains to be further investigated.
在囊性纤维化（CF）中，囊性纤维化跨膜电导调节因子（CFTR）阴离子通道中苯丙氨酸 508 缺失（F508del）导致错误折叠和过早降解。鉴于 F508del 突变对 CFTR 蛋白组装和加工的众多影响，可能需要联合使用几种药理学校正剂来治疗 CF 患者。最近，据报道胸腺肽 α-1（Tα-1）具有多种有益作用，可能为 F508del 突变的 CF 患者提供基于单一分子的治疗。这些作用包括抑制炎症、改善 F508del-CFTR 的成熟和门控，以及通过钙激活氯离子通道（CaCC）刺激氯离子分泌。鉴于这种药物的重要性，我们旨在描述 Tα-1 的作用的潜在分子机制。使用成熟的微荧光、生化和电生理技术，在 CF 患者的上皮细胞系和原代支气管上皮细胞中，对 Tα-1 的作用进行了深入分析。这两项在具有相同结果的 2 个独立实验室中进行的研究表明，Tα-1 对突变 CFTR 和 CaCC 均无活性。尽管 Tα-1 仍可能作为抗炎剂有用，但仍需进一步研究其靶向 CF 中缺陷阴离子转运的能力。
