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dc.contributor.authorLodge, Katharine M
dc.contributor.authorVassallo, Arlette
dc.contributor.authorLiu, Bin
dc.contributor.authorLong, Merete
dc.contributor.authorTong, Zhen
dc.contributor.authorNewby, Paul R
dc.contributor.authorAgha-Jaffar, Danya
dc.contributor.authorPaschalaki, Koralia
dc.contributor.authorGreen, Clara E
dc.contributor.authorBelchamber, Kylie BR
dc.contributor.authorRidger, Victoria C
dc.contributor.authorStockley, Robert A
dc.contributor.authorSapey, Elizabeth
dc.contributor.authorSummers, Charlotte
dc.contributor.authorCowburn, Andrew S
dc.contributor.authorChilvers, Edwin R
dc.contributor.authorLi, Wei
dc.contributor.authorCondliffe, Alison M
dc.date.accessioned2021-12-22T00:30:26Z
dc.date.available2021-12-22T00:30:26Z
dc.date.issued2022-04-15
dc.identifier.issn1073-449X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331668
dc.description.abstractRationale: Patients with chronic obstructive pulmonary disease (COPD) experience excess cardiovascular morbidity and mortality, and exacerbations further increase the risk of such events. COPD is associated with persistent blood and airway neutrophilia and systemic and tissue hypoxia. Hypoxia augments neutrophil elastase release, enhancing capacity for tissue injury. Objective: To determine whether hypoxia-driven neutrophil protein secretion contributes to endothelial damage in COPD. Methods: The healthy human neutrophil secretome generated under normoxic or hypoxic conditions was characterized by quantitative mass spectrometry, and the capacity for neutrophil-mediated endothelial damage was assessed. Histotoxic protein concentrations were measured in normoxic versus hypoxic neutrophil supernatants and plasma from patients experiencing COPD exacerbation and healthy control subjects. Measurements and Main Results: Hypoxia promoted PI3Kγ-dependent neutrophil elastase secretion, with greater release seen in neutrophils from patients with COPD. Supernatants from neutrophils incubated under hypoxia caused pulmonary endothelial cell damage, and identical supernatants from COPD neutrophils increased neutrophil adherence to endothelial cells. Proteomics revealed differential neutrophil protein secretion under hypoxia and normoxia, and hypoxia augmented secretion of a subset of histotoxic granule and cytosolic proteins, with significantly greater release seen in COPD neutrophils. The plasma of patients with COPD had higher content of hypoxia-upregulated neutrophil-derived proteins and protease activity, and vascular injury markers. Conclusions: Hypoxia drives a destructive "hypersecretory" neutrophil phenotype conferring enhanced capacity for endothelial injury, with a corresponding signature of neutrophil degranulation and vascular injury identified in plasma of patients with COPD. Thus, hypoxic enhancement of neutrophil degranulation may contribute to increased cardiovascular risk in COPD. These insights may identify new therapeutic opportunities for endothelial damage in COPD.
dc.publisherAmerican Thoracic Society
dc.rightsAll Rights Reserved
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.titleHypoxia Increases the Potential for Neutrophil-mediated Endothelial Damage in Chronic Obstructive Pulmonary Disease.
dc.typeArticle
dc.publisher.departmentDepartment of Medicine
dc.date.updated2021-12-20T10:11:15Z
prism.publicationNameAm J Respir Crit Care Med
dc.identifier.doi10.17863/CAM.79121
dcterms.dateAccepted2021-12-17
rioxxterms.versionofrecord10.1164/rccm.202006-2467OC
rioxxterms.versionAM
dc.contributor.orcidLodge, Katharine M [0000-0002-3203-9941]
dc.contributor.orcidSummers, Charlotte [0000-0002-7269-2873]
dc.contributor.orcidLi, Wei [0000-0002-1924-3120]
dc.identifier.eissn1535-4970
rioxxterms.typeJournal Article/Review
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idWellcome Trust (102706/Z/13/Z)
pubs.funder-project-idBritish Heart Foundation (PG/15/39/31519)
pubs.funder-project-idBritish Heart Foundation (PG/17/1/32532)
pubs.funder-project-idBritish Heart Foundation (PG/17/58/33134)
cam.issuedOnline2022-01-19
cam.orpheus.successTue Feb 01 19:02:33 GMT 2022 - Embargo updated
cam.depositDate2021-12-20
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2023-01-19


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