1
IRUS TotalDownloads
Altmetric
Hypoxia increases the potential for neutrophil-mediated endothelial damage in COPD
File | Description | Size | Format | |
---|---|---|---|---|
![]() | Published version | 848.77 kB | Adobe PDF | View/Open |
![]() | Published version | 191.03 kB | Adobe PDF | View/Open |
![]() | Published version | 531.1 kB | Adobe PDF | View/Open |
![]() | Published version | 1.29 MB | Adobe PDF | View/Open |
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