Anti-Infectives Restore ORKAMBI(R) Rescue of F508del-CFTR Function in Human Bronchial Epithelial Cells Infected with Clinical Strains of P. aeruginosa
Anti-Infectives Restore ORKAMBI(R) Rescue of F508del-CFTR Function in Human Bronchial Epithelial Cells Infected with Clinical Strains of P. aeruginosa
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DOI：
10.3390/biom10020334
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发表时间：
2020-02-01
期刊：
影响因子：
5.5
通讯作者：
Deber, Charles M.
中科院分区：
文献类型：
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作者：
Laselva, Onofrio;Stone, Tracy A.;Deber, Charles M.
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(R) (Lumacaftor-Ivacaftor) 是一种经批准的联合疗法，用于治疗囊性纤维化电导调节蛋白 (CFTR) 蛋白中携带最常见突变 F508del 的囊性纤维化 (CF) 患者。先前已表明，ORKAMBI(R) 介导的 CFTR 拯救会因预先存在的铜绿假单胞菌感染而减弱。在这里，我们发现，用实验室菌株和从 CF 患者肺痰中分离出的四种不同临床铜绿假单胞菌菌株感染 F508del-CFTR 人支气管上皮 (HBE) 细胞，会以菌株特异性方式降低 CFTR 功能 48% 至 88%。研究发现，用抗生素妥布霉素或阳离子抗菌肽 6K-F17 处理感染细胞可减少 HBE 细胞上的临床菌株细菌生长，并恢复 ORKAMBI(R) 介导的 F508del-CFTR 功能拯救。此外，还发现 6K-F17 可下调受感染的 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。结果为涉及 CFTR 调节剂和抗感染药（即妥布霉素和/或 6K-F17）的联合治疗方法提供了强有力的证据，以提高 CF 患者的总体疗效。
Chronic infection and inflammation are the primary causes of declining lung function in Cystic Fibrosis (CF) patients. ORKAMBI(R) (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(R)-mediated rescue of CFTR is reduced by a pre-existing Pseudomonas aeruginosa infection. Here, we show that the infection of F508del-CFTR human bronchial epithelial (HBE) cells with lab strain and four different clinical strains of P. aeruginosa, 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(R)-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-alpha 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.