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@article{Lodge:2021:10.1164/rccm.202006-2467OC,
author = {Lodge, K and Vassallo, A and Liu, B and Long, M and Tong, Z and Newby, P and Agha-Jaffar, D and Paschalaki, K and Green, C and Belchamber, K and Ridger, V and Stockley, R and Sapey, E and Summers, C and Cowburn, A and Chilvers, E and Li, W and Condliffe, A},
doi = {10.1164/rccm.202006-2467OC},
journal = {American Journal of Respiratory and Critical Care Medicine},
title = {Hypoxia increases the potential for neutrophil-mediated endothelial damage in COPD},
url = {http://dx.doi.org/10.1164/rccm.202006-2467OC},
volume = {205},
year = {2021}
}

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TY  - JOUR
AB  - Rationale: Chronic obstructive pulmonary disease (COPD) patients 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 characterised by quantitative mass spectrometry, and the capacity for neutrophil-mediated endothelial damage assessed. Histotoxic protein levels were measured in normoxic versus hypoxic neutrophil supernatants and plasma from exacerbating COPD patients and healthy controls.Main results: Hypoxia promoted PI3Kγ-dependent neutrophil elastase secretion, with greater release seen in neutrophils from COPD patients. 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; hypoxia augmented secretion of a subset of histotoxic granule and cytosolic proteins, with significantly greater release seen in COPD neutrophils. The plasma of COPD patients had higher content of hypoxia-upregulated neutrophil-derived proteins and protease activity, and vascular injury markers.Conclusions: Hypoxia drives a destructive ‘hyper-secretory’ neutrophil phenotype conferring enhanced capacity for endothelial injury, with a corresponding signature of neutrophil degranulation and vascular injury identified in COPD patient plasma. Thus, hypoxic enhancement of neutrophil degranulation may contribute to increased cardiovascular risk in COPD. These insights may identify new therapeutic o
AU  - Lodge,K
AU  - Vassallo,A
AU  - Liu,B
AU  - Long,M
AU  - Tong,Z
AU  - Newby,P
AU  - Agha-Jaffar,D
AU  - Paschalaki,K
AU  - Green,C
AU  - Belchamber,K
AU  - Ridger,V
AU  - Stockley,R
AU  - Sapey,E
AU  - Summers,C
AU  - Cowburn,A
AU  - Chilvers,E
AU  - Li,W
AU  - Condliffe,A
DO  - 10.1164/rccm.202006-2467OC
PY  - 2021///
SN  - 1073-449X
TI  - Hypoxia increases the potential for neutrophil-mediated endothelial damage in COPD
T2  - American Journal of Respiratory and Critical Care Medicine
UR  - http://dx.doi.org/10.1164/rccm.202006-2467OC
UR  - https://www.atsjournals.org/doi/10.1164/rccm.202006-2467OC
UR  - http://hdl.handle.net/10044/1/93615
VL  - 205
ER  -

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