{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T07:01:18Z","timestamp":1790406078834,"version":"4.1.0"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2019,4,1]],"date-time":"2019-04-01T00:00:00Z","timestamp":1554076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01HL126603"],"award-info":[{"award-number":["R01HL126603"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["MCCART15R0"],"award-info":[{"award-number":["MCCART15R0"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["111142505"],"award-info":[{"award-number":["111142505"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Peter Doherty Fellowship","award":["1141479"],"award-info":[{"award-number":["1141479"]}]},{"name":"German Ministry for Education and Research","award":["FKZ 82DZL00401"],"award-info":[{"award-number":["FKZ 82DZL00401"]}]},{"name":"German Ministry for Education and Research","award":["FKZ 82DZL004A1"],"award-info":[{"award-number":["FKZ 82DZL004A1"]}]},{"DOI":"10.13039\/100000897","name":"U.S. Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["MCCART15R0"],"award-info":[{"award-number":["MCCART15R0"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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 F\u00f6rster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>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\u2009=\u20090.55; P =\u20090.0008), 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201803-0442oc","type":"journal-article","created":{"date-parts":[[2018,10,3]],"date-time":"2018-10-03T16:43:03Z","timestamp":1538584983000},"page":"873-881","source":"Crossref","is-referenced-by-count":86,"title":["Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis"],"prefix":"10.1093","volume":"199","author":[{"given":"Camilla","family":"Margaroli","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia"},{"name":"Center for CF & Airways Disease Research, Children\u2019s Healthcare of Atlanta, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9381-326X","authenticated-orcid":false,"given":"Luke W.","family":"Garratt","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute, Perth, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamed","family":"Horati","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Erasmus University Medical Center\/Sophia Children\u2019s Hospital, Rotterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Susanne","family":"Dittrich","sequence":"additional","affiliation":[{"name":"Department of Translational Pulmonology, Translational Lung Research Center, German Center for Lung Research, and"},{"name":"Department of Pulmonology, and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3727-5131","authenticated-orcid":false,"given":"Timothy","family":"Rosenow","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute, Perth, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel T.","family":"Montgomery","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute, Perth, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9572-9686","authenticated-orcid":false,"given":"Dario L.","family":"Frey","sequence":"additional","affiliation":[{"name":"Department of Translational Pulmonology, Translational Lung Research Center, German Center for Lung Research, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milton R.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia"},{"name":"Center for CF & Airways Disease Research, Children\u2019s Healthcare of Atlanta, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5824-2171","authenticated-orcid":false,"given":"Carsten","family":"Schultz","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8145-0430","authenticated-orcid":false,"given":"Lokesh","family":"Guglani","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia"},{"name":"Center for CF & Airways Disease Research, Children\u2019s Healthcare of Atlanta, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0008-9733","authenticated-orcid":false,"given":"Anthony","family":"Kicic","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute, Perth, Australia"},{"name":"Department of Respiratory Medicine, Perth Children's Hospital, Perth, Western Australia, Australia"},{"name":"Faculty of Medicine, University of Western Australia, Perth, Western Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Emory University School of Public Health, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bob J.","family":"Scholte","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Erasmus University Medical Center\/Sophia Children\u2019s Hospital, Rotterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus A.","family":"Mall","sequence":"additional","affiliation":[{"name":"Department of Translational Pulmonology, Translational Lung Research Center, German Center for Lung Research, and"},{"name":"Berlin Institute of Health, Berlin, Germany; and"},{"name":"Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charit\u00e9-Universit\u00e4tmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hettie M.","family":"Janssens","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Erasmus University Medical Center\/Sophia Children\u2019s Hospital, Rotterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5386-8482","authenticated-orcid":false,"given":"Stephen M.","family":"Stick","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute, Perth, Australia"},{"name":"Department of Respiratory Medicine, Perth Children's Hospital, Perth, Western Australia, Australia"},{"name":"Faculty of Medicine, University of Western Australia, Perth, Western Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3526-9985","authenticated-orcid":false,"given":"Rabindra","family":"Tirouvanziam","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia"},{"name":"Center for CF & Airways Disease Research, Children\u2019s Healthcare of Atlanta, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,4,1]]},"reference":[{"key":"2026030321262304400_bib1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nrg3849","article-title":"Cystic fibrosis genetics: from molecular understanding to clinical application","volume":"16","author":"Cutting","year":"2015","journal-title":"Nat Rev Genet"},{"key":"2026030321262304400_bib2","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1164\/rccm.201004-0643OC","article-title":"Loss of cystic fibrosis transmembrane conductance regulator function produces abnormalities in tracheal development in neonatal pigs and young children","volume":"182","author":"Meyerholz","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030321262304400_bib3","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/S2213-2600(13)70026-2","article-title":"Early lung disease in cystic fibrosis","volume":"1","author":"Grasemann","year":"2013","journal-title":"Lancet Respir Med"},{"key":"2026030321262304400_bib4","first-page":"147","article-title":"Cystic fibrosis in young children: a review of disease manifestation, progression, and response to early treatment","volume-title":"J Cyst Fibros","author":"VanDevanter","year":"2016"},{"key":"2026030321262304400_bib5","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1164\/rccm.201606-1107CI","article-title":"Early lung disease in infants and preschool children with cystic fibrosis. 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