Department of Experimental Medicine (DIMES), University of Genova, 16126 Genova, Italy.
Department of Medicine, General Pathology Division, University of Verona, 37134 Verona, Italy.
Int J Mol Sci. 2021 Apr 10;22(8):3928. doi: 10.3390/ijms22083928.
The aim of this study was the identification of specific proteomic profiles, related to a restored cystic fibrosis transmembrane conductance regulator (CFTR) activity in cystic fibrosis (CF) leukocytes before and after ex vivo treatment with the potentiator VX770. We used leukocytes, isolated from CF patients carrying residual function mutations and eligible for Ivacaftor therapy, and performed CFTR activity together with proteomic analyses through micro-LC-MS. Bioinformatic analyses of the results obtained revealed the downregulation of proteins belonging to the leukocyte transendothelial migration and regulation of actin cytoskeleton pathways when CFTR activity was rescued by VX770 treatment. In particular, we focused our attention on matrix metalloproteinase 9 (MMP9), because the high expression of this protease potentially contributes to parenchyma lung destruction and dysfunction in CF. Thus, the downregulation of MMP9 could represent one of the possible positive effects of VX770 in decreasing the disease progression, and a potential biomarker for the prediction of the efficacy of therapies targeting the defect of Cl transport in CF.
本研究的目的是鉴定与囊性纤维化（CF）白细胞中囊性纤维化跨膜电导调节因子（CFTR）活性恢复相关的特定蛋白质组学特征，这些白细胞在体外用增敏剂 VX770 处理前后。我们使用白细胞，从携带残余功能突变且适合 Ivacaftor 治疗的 CF 患者中分离出来，并通过微 LC-MS 进行 CFTR 活性和蛋白质组学分析。对获得的结果进行生物信息学分析表明，当 VX770 治疗挽救 CFTR 活性时，属于白细胞跨内皮迁移和肌动蛋白细胞骨架调节途径的蛋白质下调。特别是，我们关注了基质金属蛋白酶 9（MMP9），因为这种蛋白酶的高表达可能有助于 CF 肺实质的破坏和功能障碍。因此，MMP9 的下调可能代表 VX770 降低疾病进展的可能积极影响之一，并且可能是预测针对 CF 中 Cl 转运缺陷的治疗效果的潜在生物标志物。
