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Hypoxia increases the potential for neutrophil-mediated endothelial damage in COPD

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Vassallo, Arlette 
Liu, Bin 
Long, Merete 
Newby, Paul R 


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 5 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 opportunities for endothelial damage in COPD.



cardiovascular disease, cell degranulation, neutrophil elastase, vascular endothelium, Endothelial Cells, Humans, Hypoxia, Leukocyte Elastase, Neutrophils, Pulmonary Disease, Chronic Obstructive, Vascular System Injuries

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American Journal of Respiratory and Critical Care Medicine

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American Thoracic Society
British Heart Foundation (None)
Wellcome Trust (102706/Z/13/Z)
British Heart Foundation (PG/15/39/31519)
British Heart Foundation (PG/17/1/32532)
British Heart Foundation (PG/17/58/33134)

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