Preston E Bratcher1, Steven M Rowe2, Ginger Reeves3, Tambra Roberts4, Tomasz Szul5, William T Harris6, Rabindra Tirouvanziam7, Amit Gaggar8. 1. 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. Electronic address: bratcher@uab.edu. 2. 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. Electronic address: smrowe@uab.edu. 3. Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, 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. Electronic address: greeves@peds.uab.edu. 4. Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, 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. Electronic address: troberts@peds.uab.edu. 5. 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. Electronic address: szultom@uab.edu. 6. Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, 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; Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA. Electronic address: tharris@peds.uab.edu. 7. Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA; Department of Pediatrics, Emory University, 2015 Uppergate Drive, Room 344, Atlanta, GA 30322, USA; Center for Cystic Fibrosis and Airway Disease Research, Children's Healthcare of Atlanta, 2015 Uppergate Drive, Room 344, Atlanta, GA 30322, USA. Electronic address: tirouvanziam@emory.edu. 8. 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; Medicine Service, United States Department of Veterans Affairs Medical Center, 700 19th Street South, Birmingham, AL 35233, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA. Electronic address: agaggar1@uab.edu.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: In vivo and ex vivo exposure of G551D CF leukocytes to ivacaftor resulted in an altered activation profile, suggesting mutation-specific leukocyte modulation. Published by Elsevier B.V.
BACKGROUND:Ivacaftor improves clinical outcome by potentiation of mutant G551DCFTR. Due to the presence of CFTR in monocytes and polymorphonuclear neutrophils (PMNs), we hypothesized that ivacaftor may impact leukocyte activation. METHODS: We examined blood leukocytes from G551DCF 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. RESULTS: Compared to healthy controls, G551DCF 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. CONCLUSIONS: In vivo and ex vivo exposure of G551DCF leukocytes to ivacaftor resulted in an altered activation profile, suggesting mutation-specific leukocyte modulation. Published by Elsevier B.V.
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