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dc.contributor.authorHoenderdos, Ken
dc.contributor.authorLodge, Katharineen
dc.contributor.authorHirst, RAen
dc.contributor.authorChen, Cen
dc.contributor.authorPalazzo, SGCen
dc.contributor.authorEmerenciana, Aen
dc.contributor.authorSummers, Charlotteen
dc.contributor.authorAngyal, Aen
dc.contributor.authorPorter, Len
dc.contributor.authorJuss, JKen
dc.contributor.authorO'Callaghan, Cen
dc.contributor.authorChilvers, Edwinen
dc.contributor.authorCondliffe, AMen
dc.date.accessioned2016-04-29T09:04:45Z
dc.date.available2016-04-29T09:04:45Z
dc.date.issued2016-11-01en
dc.identifier.citationThorax 2016en
dc.identifier.issn0040-6376
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/255802
dc.description.abstractBackground. The inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), but the effects of hypoxia on potentially harmful neutrophil functional responses such as degranulation are unknown. Methods and Results. Following exposure to hypoxia (0.8% oxygen, 3 kPa for 4 hours) neutrophils stimulated with inflammatory agonists (granulocyte-macrophage activating factor (GM-CSF) or platelet activating factor (PAF), and formylated peptide (fMLP)) displayed a markedly augmented (2-6 fold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9, MMP-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by co-incubation with the anti-protease alpha-1 antitrypsin; both normoxic and hypoxic supernatants impaired ciliary function. Surprisingly, the hypoxic upregulation of neutrophil degranulation was not dependent on hypoxia-inducible factor (HIF), nor was it fully reversed by inhibition of phospholipase C (PLC) signaling. Hypoxia augmented the resting and cytokinestimulated phosphorylation of Akt, and inhibition of phosphoinositide 3-kinase (PI3K)γ 3 (but not other PI3K isoforms) prevented the hypoxic upregulation of neutrophil elastase release. Conclusion. Hypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion.
dc.description.sponsorshipSupported by the British Lung Foundation, Papworth Hospital NHS Foundation Trust, BBSRC and the Cambridge NIHR-Biomedical Research Centre. CS is in receipt of a Wellcome Trust Early Postdoctoral Research Fellowship for Clinician Scientists [WT101692MA].
dc.languageENGen
dc.language.isoenen
dc.publisherBMJ Publishing Group
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAirway Epitheliumen
dc.subjectCOPD ÀÜ Mechanismsen
dc.subjectCystic Fibrosisen
dc.subjectInnate Immunityen
dc.subjectNeutrophil Biologyen
dc.subjectRespiratory Infectionen
dc.titleHypoxia upregulates neutrophil degranulation and potential for tissue injury.en
dc.typeArticle
dc.provenanceOA-8504
prism.endingPage1038
prism.issueIdentifier11en
prism.publicationDate2016en
prism.publicationNameThoraxen
prism.startingPage1030
prism.volume71en
dc.rioxxterms.funderBBSRC
dc.rioxxterms.funderNIHR
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.projectidWT101692MA
dcterms.dateAccepted2016-04-04en
rioxxterms.versionofrecord10.1136/thoraxjnl-2015-207604en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2016-11-01en
dc.contributor.orcidSummers, Charlotte [0000-0002-7269-2873]
dc.contributor.orcidChilvers, Edwin [0000-0002-4230-9677]
dc.identifier.eissn1468-3296
rioxxterms.typeJournal Article/Reviewen
cam.issuedOnline2016-08-31en
cam.orpheus.successThu Jan 30 12:54:22 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2099-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International