布洛芬拯救突变型囊性纤维化跨膜电导调节蛋白的运输。
Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking.
机构信息
Cystic Fibrosis Translational Research Center, Dept. of Biochemistry, McGill University, Montreal, Quebec H3G1Y6, Canada.
Cystic Fibrosis Translational Research Center, Dept. of Physiology, McGill University, Montreal, Quebec H3G1Y6, Canada.
出版信息
J Cyst Fibros. 2015 Jan;14(1):16-25. doi: 10.1016/j.jcf.2014.06.001. Epub 2014 Jun 25.
BACKGROUND
Small molecules as shown by VX809 can rescue the mislocalization of F508del-CFTR. The aim of this study was to identify correctors with a clinical history and their targets of action.
METHODS
CFTR correctors were screened using two F508del-CFTR expressing cell based HTS assays. Electrophysiological studies using CFBE41o(-) and HBE cells and in-vivo mouse assays confirmed CFTR rescue. The target of action was attained using pharmacological inhibitors and siRNA to specific genes.
RESULTS
Ibuprofen was identified as a CFTR corrector. Ibuprofen treatment of polarized CFBE41o(-) monolayers increased the short-circuit current (Isc) response to stimulation. In vivo CF mice treatment with ibuprofen restored the CFTR trafficking. SiRNA knock down of cyclooxygenase expression caused partial F508del-CFTR correction.
CONCLUSION
These studies show that ibuprofen is a CFTR corrector and that it causes correction by COX-1 inhibition. Hence ibuprofen may be suitable to be part of a future CF combination therapy.
背景
VX809 等小分子可纠正 F508del-CFTR 的定位错误。本研究旨在寻找具有临床应用史的校正剂及其作用靶点。
方法
采用两种 F508del-CFTR 表达细胞的高通量筛选检测方法筛选 CFTR 校正剂。采用 CFBE41o(-) 和 HBE 细胞进行电生理研究，并在体内小鼠模型中进行验证，以确认 CFTR 的恢复情况。采用药理学抑制剂和特定基因的 siRNA 来确定作用靶点。
结果
布洛芬被鉴定为 CFTR 校正剂。布洛芬处理极化 CFBE41o(-) 单层细胞可增加刺激引起的短路电流（Isc）反应。体内 CF 小鼠用布洛芬处理可恢复 CFTR 转运。环氧合酶表达的 siRNA 敲低可部分纠正 F508del-CFTR。
结论
这些研究表明布洛芬是 CFTR 校正剂，通过 COX-1 抑制发挥作用。因此，布洛芬可能适合作为未来 CF 联合治疗的一部分。
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