Division of Molecular Medicine, Research Institute, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Biomolecules. 2020 Feb 19;10(2):334. doi: 10.3390/biom10020334.
Chronic infection and inflammation are the primary causes of declining lung function in Cystic Fibrosis (CF) patients. ORKAMBI (Lumacaftor-Ivacaftor) is an approved combination therapy for Cystic Fibrosis (CF) patients bearing the most common mutation, F508del, in the cystic fibrosis conductance regulator (CFTR) protein. It has been previously shown that ORKAMBI-mediated rescue of CFTR is reduced by a pre-existing infection. Here, we show that the infection of F508del-CFTR human bronchial epithelial (HBE) cells with lab strain and four different clinical strains of isolated from the lung sputum of CF patients, decreases CFTR function in a strain-specific manner by 48 to 88%. The treatment of infected cells with antibiotic tobramycin or cationic antimicrobial peptide 6K-F17 was found to decrease clinical strain bacterial growth on HBE cells and restore ORKAMBI-mediated rescue of F508del-CFTR function. Further, 6K-F17 was found to downregulate the expression of pro-inflammatory cytokines, interleukin (IL)-8, IL-6, and tumor necrosis factor-α in infected HBE cells. The results provide strong evidence for a combination therapy approach involving CFTR modulators and anti-infectives (i.e., tobramycin and/or 6K-F17) to improve their overall efficacy in CF patients.
慢性感染和炎症是囊性纤维化（CF）患者肺功能下降的主要原因。ORKAMBI（Lumacaftor-Ivacaftor）是一种已批准的囊性纤维化（CF）治疗药物，适用于携带囊性纤维化跨膜电导调节因子（CFTR）蛋白最常见突变 F508del 的 CF 患者。先前的研究表明，ORKAMBI 介导的 CFTR 恢复会被先前存在的感染所削弱。在这里，我们表明，从 CF 患者的肺部痰液中分离出来的实验室菌株和四种不同的临床菌株感染 F508del-CFTR 人支气管上皮（HBE）细胞，以菌株特异性的方式将 CFTR 功能降低 48%至 88%。研究发现，用抗生素妥布霉素或阳离子抗菌肽 6K-F17 处理感染细胞，可以减少 HBE 细胞上临床分离株细菌的生长，并恢复 ORKAMBI 对 F508del-CFTR 功能的修复作用。此外，6K-F17 还被发现可以下调感染的 HBE 细胞中促炎细胞因子白细胞介素（IL）-8、IL-6 和肿瘤坏死因子-α的表达。这些结果为涉及 CFTR 调节剂和抗感染药物（即妥布霉素和/或 6K-F17）的联合治疗方法提供了有力证据，以提高其在 CF 患者中的整体疗效。
