Hypoxia Increases the Potential for Neutrophil-mediated Endothelial Damage in Chronic Obstructive Pulmonary Disease

Abstract

Scientific knowledge on the subject: COPD is characterised by persistent neutrophilia in the setting of local and systemic hypoxia, and is associated with excess cardiovascular disease, even allowing for known risk factors. Neutrophils accumulating in areas of inflammation and microcirculatory impairment experience profound hypoxia, which prolongs their survival and increases their secretory responses. Thus, hypoxic neutrophils have increased potential to cause endothelial injury but their role in mediating the increased cardiovascular risk in COPD is poorly understood.What this study adds to the field: Herein we show that hypoxia augments the ability of neutrophils to selectively secrete a subset of histotoxic proteins capable of AJRCCM Articles in Press.

Exploring the significance of RNA N6 methyladenosine regulatory factor in the diagnosis and subtype classification of chronic obstructive pulmonary disease based on GEO database

“…Through the analysis of immune cell infiltration, it was found that compared with the high expression of WTAP, the low expression group of wtap was significantly higher in neutrophils and eosinophils.It can be concluded that m6A subtype is related to neutrophil extracellular trap (NET) and eosinophil extracellular trap (EET) caused by neutrophils and eosinophils.The clusterB subtype is related to monocyte extracellular trap (MOET) caused by monocytes.EET is composed of DNA fiber network released after activation of eosinophils and granular proteases such as eosinophil cationic protein (ECP) and major basic protein (EOM).Studies have found that activated eosinophils in severe asthma can activate type 2 innate immune lymphocytes through EET to induce steroid resistance [42].Net is a reticular extracellular structure composed of extracellular DNA released by activated neutrophils and neutrophil elastase (NE), myeloperoxidase (MPO) and other degradation enzymes. Studies have shown that enhanced net in COPD patients can be related to airflow restriction and lung tissue injury in COPD patients by activating airway neutrophil inflammation [43].In addition, the study found that MOET can be activated by reactive oxygen species (ROS), showing a similar morphology to net releasing myeloperoxidase (MPO), lactoferrin (LF), elastase and so on, but the release of MOET does not depend on MPO activity [44].Other studies have found that hypoxia can cooperate with inflammatory mediators to promote the release of tissue toxic proteins such as neutrophil elastase (NE), myeloperoxidase (MPO), vascular injury or activated intercellular adhesion molecule (ICAM-1) in COPD to induce endothelial injury [45].Other studies have shown that C5AR1 positive neutrophils can also release inflammatory factors such as IL1 β、 TNF α、ENO1 to promote the growth of breast cancer in patients with breast cancer but m6A methylated WTAP can eliminate this process [46].In addition, leukocyte family chemokine (CXCR1) in COPD patients can bind with ligand IL-8 to activate neutrophil chemotaxis, phospholipase D activation and respiratory burst to induce airflow restriction in COPD patients and promote inflammatory response [47].The global initiative for chronic obstructive pulmonary disease (gold) pointed out that the increased eosinophils in the blood and sputum of COPD patients can not only predict the risk of disease exacerbation, but also predict the effect of glucocorticoid treatment [48].In addition, studies have shown that the increase of blood eosinophils in COPD patients is positively correlated with FeNO value and eosinophils have better lung function performance [49].…”

Hypoxia Can Make Neutrophils Hyper, Potentially Wreaking Havoc during Exacerbations in Chronic Obstructive Pulmonary Disease

“…These results led to a very interesting series of studies (4). Neutrophils from either healthy donors or subjects with non-exacerbating COPD and exposed to severe (0.8% O 2 ) hypoxia for 4 hours released more elastase than neutrophils kept in a normoxic environment (21% O 2 ), but only after brief stimulation with combined PAF and fMLP at the end of the hypoxic period.…”

“…In this issue of the Journal , Lodge and colleagues (pp. 903–916 ) ask, what does hypoxia do to neutrophil function that injures endothelial cells (ECs) ( 4 )? Their initial studies revealed a variable but significant increase in the cleavage products of NE (neutrophil elastase) and proteinase 3 activity in the plasma of subjects with exacerbating COPD compared with healthy donors.…”

“…Second, the authors mimicked in vivo circumstances by incubating ECs with supernatants from neutrophils exposed to hypoxia and then fMLP/PAF ( 4 ). Supernatants from hypoxic neutrophils induced more detachment and death of cultured human ECs from either the pulmonary artery or the lung microvasculature.…”

“…The third series of studies examined neutrophils from participants with exacerbating COPD or healthy donors ( 4 ). The authors’ data suggest that circulating neutrophils from subjects with COPD were not primed during exacerbations.…”