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

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Title: Hypoxia increases the potential for neutrophil-mediated endothelial damage in COPD
Authors: Lodge, K
Vassallo, A
Liu, B
Long, M
Tong, Z
Newby, P
Agha-Jaffar, D
Paschalaki, K
Green, C
Belchamber, K
Ridger, V
Stockley, R
Sapey, E
Summers, C
Cowburn, A
Chilvers, E
Li, W
Condliffe, A
Item Type: Journal Article
Abstract: 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 opportunities for endothelial damage in COPD.
Date of Acceptance: 17-Dec-2021
URI: http://hdl.handle.net/10044/1/93615
DOI: 10.1164/rccm.202006-2467OC
ISSN: 1073-449X
Publisher: American Thoracic Society
Journal / Book Title: American Journal of Respiratory and Critical Care Medicine
Volume: 205
Issue: 8
Copyright Statement: © 2022 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.202006-2467OC on January 19, 2022. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License.
Sponsor/Funder: National Heart and Lung Foundation
The Academy of Medical Sciences
British Heart Foundation
Funder's Grant Number: WHZZ_P78733
SGL024\1086
PG/19/75/34686
Keywords: Science & Technology
Life Sciences & Biomedicine
Critical Care Medicine
Respiratory System
General & Internal Medicine
cell degranulation
neutrophil elastase
vascular endothelium
cardiovascular disease
GELATINASE-ASSOCIATED LIPOCALIN
PLATELET-ACTIVATING-FACTOR
CYCLOPHILIN
DEGRANULATION
SECRETION
EMPHYSEMA
ELASTASE
SMOKERS
AIRWAYS
SPUTUM
cardiovascular disease
cell degranulation
neutrophil elastase
vascular endothelium
Endothelial Cells
Humans
Hypoxia
Leukocyte Elastase
Neutrophils
Pulmonary Disease, Chronic Obstructive
Vascular System Injuries
Neutrophils
Endothelial Cells
Humans
Pulmonary Disease, Chronic Obstructive
Leukocyte Elastase
Vascular System Injuries
Hypoxia
Respiratory System
11 Medical and Health Sciences
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



This item is licensed under a Creative Commons License Creative Commons