Effects of ivacaftor on systemic inflammation and the plasma proteome in people with CF and G551D |
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| Affiliation: | 1. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States;2. Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, United States;3. Department of Medicine, Pediatrics and Cell Developmental and Integrative Biology, University of Alabama Birmingham, Birmingham, AL, England;4. Department of Pediatrics, University of Washington, Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle, WA, United States;1. Imaging Department, Hopital Nord, APHM, Aix Marseille University;2. Aix Marseille Univ, LIIE, Marseille, France;3. Aix Marseille Univ, CERIMED, Marseille, France;4. Service de Pneumologie et équipe de transplantation pulmonaire, Centre de Ressources et de Compétences de la Mucoviscidose (CRCM) Adulte, AP-HM Hôpital Nord,13015, Marseille France;5. Aix Marseille Université, Service de radiologie, La Timone Hôpital, 264 rue Saint Pierre, 13005 Marseille;6. Service d''anatomie et cytologie pathologiques, Hôpital Nord, chemin des Bourrely, 13015 Marseille, France;7. U1068- CRCM, Aix Marseille université, 13015 Marseille, France;8. Service de chirurgie thoracique et Transplantation Pulmonaire, hôpital Nord, chemin des Bourrely, 13015 Marseille, France;9. Aix Marseille Univ, APHM, INSERM, IRD, SESSTIM, ISSPAM, Hop Timone, Biostatistics department, BIOSTIC, Marseille, F-13005, France;1. Department of Pediatrics, Division of Pediatric Pulmonology, Johns Hopkins University, Baltimore, MD, United States of America;2. Department of Pediatrics, Division of General Pediatrics, Johns Hopkins University, Baltimore, MD, United States of America;3. Department of Medicine, Division of Pulmonary & Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States of America;4. Department of Pediatrics, Pediatric Pulmonary Section, Baylor College of Medicine, Houston, TX, United States of America;1. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA;2. Department of Pediatrics, University of Nebraska Medical Center, Children''s Hospital and Medical Center, Omaha, NE, USA;3. Department of Pediatrics, UNC Children''s, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA;4. Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA;5. Department of Paediatrics, Erasmus MC – Sophia Children''s Hospital, University Medial Center Rotterdam, Netherlands;6. Department of Radiology and Nuclear Medicine, Erasmus MC – Sophia Children''s Hospital, University Medial Center Rotterdam, Netherlands;7. The Centre for Microscopy, Characterisation and Analysis, The University of Western Australia, Nedlands, Western Australia;8. Children''s Lung Health, Wal-yan Respiratory Research Centre, Telethon Kids Institute and School of Physiotherapy and Exercise Science, Curtin University, Perth, Australia;9. Department of Pediatrics, Washington University, St. Louis Children''s Hospital, St. Louis, MO, USA;10. Department of Pediatrics, University of Western Australia, Telethon Kids Institute, Perth, Australia;11. Department of Respiratory and Sleep Medicine, Royal Children''s Hospital, Parkville, Australia;12. Infection and Immunity, Murdoch Children''s Research Institute, Parkville, Australia;13. Department of Paediatrics, University of Melbourne, Parkville, Australia;1. Adult CF Unit, Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool L14 3PE, UK;2. Department of Dermatology, Broadgreen Hospital, Liverpool University Hospitals NHS Foundation Trust, Thomas Drive, Liverpool L14 3LB, UK;3. Institute of Infection and Global Health, University of Liverpool, Liverpool, UK;4. Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK;1. NIHR Academic Clinical Fellow, Leeds teaching Hospitals NHS Foundation Trust, United Kingdom;2. Cystic Fibrosis/Respiratory Medicine Consultant, Bristol Adult Cystic Fibrosis Centre, United Kingdom;1. Microbiomes Microbes and Informatics Group, Organisms and Environment Division, School of Biosciences, Cardiff University, Sir Martin Evans Building, Park Place, Cardiff, UK;2. Department of Paediatric Respiratory Medicine, Noah''s Ark Children''s Hospital for Wales, Cardiff, UK;3. School of Medicine, Cardiff University, UK;4. Department of Paediatric Physiotherapy, Noah''s Ark Children''s Hospital for Wales, Cardiff, UK;5. Molecular Biosciences Division, School of Biosciences, Cardiff University, Sir Martin Evans Building, Park Place, Cardiff, UK |
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| Abstract: | BackgroundIvacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator for people with CF and the G551D mutation. We aimed to investigate the biology of CFTR modulation and systemic effects of CFTR restoration by examining changes in circulating measurements of inflammation and growth and novel proteins with ivacaftor treatment.MethodsBlood samples from 64 CF subjects with G551D-CFTR were analyzed for inflammatory and growth-related proteins at baseline, 1 and 6 months after ivacaftor initiation. In 30 subjects, plasma was assayed for 1,322 proteins using the SomaScan proteomic platform at baseline and 6 months post-ivacaftor. Correlations with clinical outcomes were assessed.Measurements and Main ResultsSignificant reductions in high mobility group box-1 protein (HMGB-1), calprotectin, serum amyloid A, and granulocyte colony-stimulating factor (G-CSF), and an increase in insulin-like growth factor (IGF-1) occurred 1 month after ivacaftor. This treatment effect was sustained at 6 months for HMGB-1 and calprotectin. Correcting for multiple comparisons in the proteomic analysis, 9 proteins (albumin, afamin, leptin, trypsin, pancreatic stone protein [PSP], pituitary adenylate cyclase-activating polypeptide-38, repulsive guidance molecule A [RGMA], calreticulin, GTPase KRas) changed significantly with ivacaftor. Proteins changing with treatment are involved in lipid digestion and transport and extracellular matrix organization biological processes. Reductions in calprotectin and G-CSF and increases in calreticulin, and RGMA correlated with improved lung function, while increasing IGF-1, leptin and afamin and decreasing PSP correlated with increased weight.ConclusionsIvacaftor led to changes in inflammatory, lipid digestion, and extracellular matrix proteins, lending insights into the extrapulmonary effects of CFTR modulation. |
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