Bratcher Preston E, Rowe Steven M, Reeves Ginger, Roberts Tambra, Szul Tomasz, Harris William T, Tirouvanziam Rabindra, Gaggar Amit
Department of Medicine and Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, 424 THT, 1900 University Blvd, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA.
Department of Medicine and Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, 424 THT, 1900 University Blvd, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, Birmingham, AL 35294, USA; University of Alabama at Birmingham, UAB Lung Health Center, 526 20th Street South, Birmingham, AL 35294, USA; Department of Pediatrics at Children's of Alabama, University of Alabama at Birmingham, 1600 7th Avenue South, Birmingham, AL 35233, USA; Department of Cell, Developmental, and Integrative Biology, THT 926, 1720 2nd Avenue South, Birmingham, AL 35294, USA.
J Cyst Fibros. 2016 Jan;15(1):67-73. doi: 10.1016/j.jcf.2015.02.010. Epub 2015 Mar 11.
Ivacaftor improves clinical outcome by potentiation of mutant G551D CFTR. Due to the presence of CFTR in monocytes and polymorphonuclear neutrophils (PMNs), we hypothesized that ivacaftor may impact leukocyte activation.
We examined blood leukocytes from G551D CF subjects prior to and at one and six months after receiving ivacaftor. Blood leukocytes from ivacaftor-naïve G551D, F508del, and healthy controls were also treated with ivacaftor ex vivo to assess mutation-specific effects.
Compared to healthy controls, G551D CF subjects had significantly higher expression of active CD11b on PMNs and of CD63 on monocytes, which were normalized by in vivo ivacaftor treatment. Ex vivo exposure to ivacaftor of blood cells from G551D, but not F508del and healthy subjects, resulted in changes in CXCR2 and CD16 expression on PMNs.
In vivo and ex vivo exposure of G551D CF leukocytes to ivacaftor resulted in an altered activation profile, suggesting mutation-specific leukocyte modulation.
依伐卡托通过增强突变型G551D囊性纤维化跨膜传导调节因子（CFTR）改善临床结局。由于单核细胞和多形核中性粒细胞（PMN）中存在CFTR，我们推测依伐卡托可能影响白细胞激活。
我们检测了接受依伐卡托治疗前、治疗1个月和6个月时G551D型囊性纤维化（CF）患者的血液白细胞。还对未接受过依伐卡托治疗的G551D型、F508del型CF患者及健康对照者的血液白细胞进行体外依伐卡托处理，以评估突变特异性效应。
与健康对照相比，G551D型CF患者PMN上活性CD11b及单核细胞上CD63的表达显著更高，体内依伐卡托治疗可使其恢复正常。G551D型CF患者（而非F508del型CF患者及健康受试者）的血细胞体外暴露于依伐卡托后，PMN上CXCR2和CD16的表达发生变化。
G551D型CF白细胞体内和体外暴露于依伐卡托均导致激活状态改变，提示存在突变特异性白细胞调节。
