Neutrophil dysfunction in cystic fibrosis |
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| Institution: | 1. Massachusetts General Hospital, Department of Pediatrics, Pulmonary Division, Boston, MA, United States;2. Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, MA, United States;3. Massachusetts General Hospital, Center for Engineering in Medicine, Boston, MA, United States;4. Massachusetts General Hospital, Wellman Center for Photomedicine, Boston, MA, United States;5. Harvard Medical School, Department of Pediatrics, Boston, MA, United States;6. Harvard Medical School, Department of Surgery, Boston, MA, United States;7. Harvard Medical School, Department of Pathology, Boston, MA, United States;8. Harvard Medical School, Department of Dermatology, Boston, MA, United States;9. Shriners Hospital for Children, Boston, MA, United States;1. Department of Paediatric Respiratory Medicine, Royal Brompton Hospital and National Heart Lung Institute Imperial College London, UK;2. UCL Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK;3. Bristol Royal Hospital for Children, Bristol, UK;4. Stanford School of Law, USA;5. Clinical Trials Accelerator Platform, Cystic Fibrosis Trust, UK;6. Cystic Fibrosis Trust, UK;7. UK CF Registry, Cystic Fibrosis Trust and Department of Paediatric Respiratory Medicine, Royal Brompton Hospital and National Heart Lung Institute, Imperial College London, UK;8. Department of Adult Cystic Fibrosis, Royal Brompton Hospital and National Heart Lung Institute Imperial College London;1. National Heart Lung Institute, Imperial College London, London, United Kingdom;2. Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield Trust, London, United Kingdom;3. School of Medicine, Dentistry and Biomedical Sciences, Queen''s University, Belfast, United Kingdom;4. Department of Adult Cystic Fibrosis, Royal Brompton and Harefield Trust, London, United Kingdom;5. Clinical Trials Accelerator Platform, Cystic Fibrosis Trust, United Kingdom;6. RTI Health Solutions, Health Preference Assessment, Belfast, United Kingdom;7. Queen Elizabeth Hospital, Birmingham, United Kingdom;1. Respiratory and Sleep Medicine, Royal Children''s Hospital, Melbourne, Australia;2. Respiratory, Murdoch Children''s Research Institute, Melbourne, Australia;3. Department of Paediatrics, University of Melbourne, Melbourne, Australia;4. Wal-yan Respiratory Research Centre, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia;5. Division of Paediatrics and Child Health, Faculty of Medicine, The University of Western Australia, Perth, Australia;6. Department of Respiratory Medicine and Sleep Medicine, Perth Children''s Hospital, Perth, Australia;1. Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, United States;2. Department of Medicine, Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, Atlanta, GA, United States;3. Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, University of Pittsburgh, Pittsburgh, PA, United States;4. Department of Internal Medicine, Division of Pulmonary and Critical Care, UT Southwestern, Dallas, TX, United States;5. School of Nursing, University of Alabama at Birmingham, Birmingham, AL, United States;6. Departments of Medicine and Pediatrics, Divisions of Pulmonary Sciences and Critical Care Medicine and Pediatric Pulmonology, University of Colorado Anschutz Medical Campus, Denver, CO, United States;7. Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States;8. Department of Pediatrics, Division of Pulmonology, Boston Children''s Hospital, Harvard Medical School, Boston, MA, United States;9. Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, United States;10. Division of Urology, Seattle Children''s Hospital, University of Washington, Seattle, WA, United States;11. Assistant district attorney, Rochester, NY, United States;12. Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, University of Alabama at Birmingham, Birmingham, AL, United States;13. Department of Pediatrics, Division of Adolescent and Young Adult Medicine, University of Pittsburgh, Pittsburgh, PA, United States;1. Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern Unviersity Hospital, University of Bern, Switzerland;2. Graduate School for Health Sciences, University of Bern, Switzerland;3. University of Basel Children''s Hospital (UKBB), Basel, Switzerland;4. Division of Respiratory Medicine, University Children''s Hospital Zurich, Switzerland;5. Division of Respiratory Medicine, Children''s Hospital Aarau, Switzerland;6. Department of Paediatrics, Respiratory Unit, Lausanne University Hospital, Lausanne, Switzerland;7. Institute for Social and Preventive Medicine, University of Bern, Switzerland |
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| Abstract: | BackgroundExcessive neutrophil inflammation is the hallmark of cystic fibrosis (CF) airway disease. Novel technologies for characterizing neutrophil dysfunction may provide insight into the nature of these abnormalities, revealing a greater mechanistic understanding and new avenues for CF therapies that target these mechanisms.MethodsBlood was collected from individuals with CF in the outpatient clinic, CF individuals hospitalized for a pulmonary exacerbation, and non-CF controls. Using microfluidic assays and advanced imaging technologies, we characterized 1) spontaneous neutrophil migration using microfluidic motility mazes, 2) neutrophil migration to and phagocytosis of Staphylococcal aureus particles in a microfluidic arena, 3) neutrophil swarming on Candida albicans clusters, and 4) Pseudomonas aeruginosa-induced neutrophil transepithelial migration using micro-optical coherence technology (µOCT).ResultsParticipants included 44 individuals: 16 Outpatient CF, 13 Hospitalized CF, and 15 Non-CF individuals. While no differences were seen with spontaneous migration, CF neutrophils migrated towards S. aureus particles more quickly than non-CF neutrophils (p < 0.05). CF neutrophils, especially Hospitalized CF neutrophils, generated significantly larger aggregates around S. aureus particles over time. Hospitalized CF neutrophils were more likely to have dysfunctional swarming (p < 0.01) and less efficient clearing of C. albicans (p < 0.0001). When comparing trans-epithelial migration towards Pseudomonas aeruginosa epithelial infection, Outpatient CF neutrophils displayed an increase in the magnitude of transmigration and adherence to the epithelium (p < 0.05).ConclusionsAdvanced technologies for characterizing CF neutrophil function reveal significantly altered migratory responses, cell-to-cell clustering, and microbe containment. Future investigations will probe mechanistic basis for abnormal responses in CF to identify potential avenues for novel anti-inflammatory therapeutics. |
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