Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages
File(s)
Author(s)
Type
Journal Article
Abstract
Background: Increased reactive oxygen species (ROS) have been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD).
Objective: This study examined the effect of exogenous and endogenous oxidative stress on macrophage phagocytosis in patients with COPD.
Methods: Monocyte-derived macrophages (MDM) were generated from non-smoker, smoker and COPD subjects, differentiated in either GM-CSF (G-Mϕ) or M-CSF (M-Mϕ). Alveolar macrophages were isolated from lung tissue or bronchoalveolar lavage. Macrophages were incubated +/- 200M H2O2 for 24 hours, then exposed to fluorescently-labelled H. influenzae or S. pneumoniae for 4 hours, after which phagocytosis, mitochondrial ROS (mROS), and mitochondrial membrane potential (m) were measured.
Results: Phagocytosis of bacteria was significantly decreased in both G-Mϕ and M-Mϕ from COPD patients, compared to non-smoker controls. In non-smokers and smokers, bacterial phagocytosis did not alter mROS or m, however in COPD, phagocytosis increased early mROS and decreased m in both G-Mϕ and M-Mϕ. Exogenous oxidative stress reduced phagocytosis in non-smoker and COPD alveolar macrophages, and non-smoker MDM, associated with reduced mROS production.
Conclusion: COPD macrophages show defective phagocytosis, which is associated with altered mitochondrial function and an inability to regulate mROS production. Targeting mitochondrial dysfunction may restore the phagocytic defect in COPD.
Objective: This study examined the effect of exogenous and endogenous oxidative stress on macrophage phagocytosis in patients with COPD.
Methods: Monocyte-derived macrophages (MDM) were generated from non-smoker, smoker and COPD subjects, differentiated in either GM-CSF (G-Mϕ) or M-CSF (M-Mϕ). Alveolar macrophages were isolated from lung tissue or bronchoalveolar lavage. Macrophages were incubated +/- 200M H2O2 for 24 hours, then exposed to fluorescently-labelled H. influenzae or S. pneumoniae for 4 hours, after which phagocytosis, mitochondrial ROS (mROS), and mitochondrial membrane potential (m) were measured.
Results: Phagocytosis of bacteria was significantly decreased in both G-Mϕ and M-Mϕ from COPD patients, compared to non-smoker controls. In non-smokers and smokers, bacterial phagocytosis did not alter mROS or m, however in COPD, phagocytosis increased early mROS and decreased m in both G-Mϕ and M-Mϕ. Exogenous oxidative stress reduced phagocytosis in non-smoker and COPD alveolar macrophages, and non-smoker MDM, associated with reduced mROS production.
Conclusion: COPD macrophages show defective phagocytosis, which is associated with altered mitochondrial function and an inability to regulate mROS production. Targeting mitochondrial dysfunction may restore the phagocytic defect in COPD.
Date Issued
2019-10-10
Date Acceptance
2019-06-28
Citation
European Respiratory Journal, 2019, 54 (4), pp.1-14
ISSN
0903-1936
Publisher
European Respiratory Society
Start Page
1
End Page
14
Journal / Book Title
European Respiratory Journal
Volume
54
Issue
4
Copyright Statement
©ERS 2019 https://www.ersjournals.com/user-licence
Sponsor
Medical Research Council (MRC)
Identifier
https://erj.ersjournals.com/content/54/4/1802244
Grant Number
G1001372
Subjects
Science & Technology
Life Sciences & Biomedicine
Respiratory System
OBSTRUCTIVE PULMONARY-DISEASE
STREPTOCOCCUS-PNEUMONIAE
HAEMOPHILUS-INFLUENZAE
ALVEOLAR MACROPHAGES
LUNG
INFLAMMATION
POLARIZATION
MODULATION
MECHANISMS
RESPONSES
COPD-MAP consortium
Respiratory System
11 Medical and Health Sciences
Publication Status
Published
Date Publish Online
2019-10-10