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dc.contributor.authorMargaroli, C.
dc.contributor.authorGarratt, L.W.
dc.contributor.authorHorati, H.
dc.contributor.authorDittrich, A.S.
dc.contributor.authorRosenow, T.
dc.contributor.authorMontgomery, S.T.
dc.contributor.authorFrey, D.L.
dc.contributor.authorBrown, M.R.
dc.contributor.authorSchultz, C.
dc.contributor.authorGuglani, L.
dc.contributor.authorKicic, Anthony
dc.contributor.authorPeng, L.
dc.contributor.authorScholte, B.J.
dc.contributor.authorMall, M.A.
dc.contributor.authorJanssens, H.M.
dc.contributor.authorStick, S.M.
dc.contributor.authorTirouvanziam, R.
dc.date.accessioned2019-11-09T20:40:33Z
dc.date.available2019-11-09T20:40:33Z
dc.date.issued2019
dc.identifier.citationMargaroli, C. and Garratt, L.W. and Horati, H. and Dittrich, A.S. and Rosenow, T. and Montgomery, S.T. and Frey, D.L. et al. 2019. Elastase exocytosis by airway neutrophils is associated with early lung damage in children with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 199 (7): pp. 873-881.
dc.identifier.urihttp://hdl.handle.net/20.500.11937/76779
dc.identifier.doi10.1164/rccm.201803-0442OC
dc.description.abstract

Copyright © 2019 by the American Thoracic Society. Rationale: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown. Objectives: To measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF. Methods: We measured lung damage using chest computed tomography coupled with the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis scoring system. Concomitantly, we phenotyped blood and BAL fluid leukocytes by flow and image cytometry, and measured free extracellular NE activity using spectrophotometric and Förster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects. Measurements and Main Results: Children with CF but not disease control children harbored BAL fluid neutrophils with high exocytosis of primary granules, before the detection of bronchiectasis. This measure of NE exocytosis correlated with lung damage (R = 0.55; P = 0.0008), whereas the molecular measure of free extracellular NE activity did not. This discrepancy may be caused by the inhibition of extracellular NE by BAL fluid antiproteases and its binding to leukocytes. Conclusions: NE exocytosis by airway neutrophils occurs in all children with CF, and its cellular measure correlates with early lung damage. These findings implicate live airway neutrophils in early CF pathogenesis, which should instruct biomarker development and antiinflammatory therapy in children with CF.

dc.languageEnglish
dc.publisherAMER THORACIC SOC
dc.subjectScience & Technology
dc.subjectLife Sciences & Biomedicine
dc.subjectCritical Care Medicine
dc.subjectRespiratory System
dc.subjectGeneral & Internal Medicine
dc.subjectair trapping
dc.subjectdegranulation
dc.subjectmucus plugging
dc.subjectproteolysis
dc.subjectscavenging
dc.subjectYOUNG-CHILDREN
dc.subjectINFLAMMATORY RESPONSES
dc.subjectINNATE IMMUNITY
dc.subjectDISEASE
dc.subjectINFANTS
dc.subjectPROGRESSION
dc.subjectDIAGNOSIS
dc.subjectBRONCHIECTASIS
dc.subjectMACROPHAGES
dc.subjectPSEUDOMONAS
dc.titleElastase exocytosis by airway neutrophils is associated with early lung damage in children with cystic fibrosis
dc.typeJournal Article
dcterms.source.volume199
dcterms.source.number7
dcterms.source.startPage873
dcterms.source.endPage881
dcterms.source.issn1073-449X
dcterms.source.titleAmerican Journal of Respiratory and Critical Care Medicine
dc.date.updated2019-11-09T20:40:31Z
curtin.departmentSchool of Public Health
curtin.accessStatusFulltext not available
curtin.facultyFaculty of Health Sciences
curtin.contributor.orcidKicic, Anthony [0000-0002-0008-9733]
dcterms.source.eissn1535-4970
curtin.contributor.scopusauthoridKicic, Anthony [6507472922]


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