Kylie B. R. Belchamber, Richa Singh, Craig M. Batista, Moira K. Whyte, David H. Dockrell, Iain Kilty, Matthew J. Robinson, Jadwiga A. Wedzicha, Peter J. Barnes, Louise E. Donnelly COPDMAP consortium
European Respiratory Journal 2019; DOI: 10.1183/13993003.02244-2018
Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages
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 +/− 200 µM H2O2 for 24 h, then exposed to fluorescently-labelled H. influenzae or S. pneumoniae for 4 h, after which phagocytosis, mitochondrial ROS (mROS), and mitochondrial membrane potential (ΔΨm) 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 ΔΨm, however in COPD, phagocytosis increased early mROS and decreased ΔΨm 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.
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Dockrell reports grants from MRC and Wellcome Trust during the conduct of the study; grants from GSK, advisory board role for Lilly and ViiV, non-financial support from Novartis, other from Astra Zeneca, MedImmune, RedX Pharmaceuticals, Sygnature Discovery, Pfizer, GSK, outside the submitted work.
Conflict of interest: Dr. Wedzicha reports grants from GSK, grants from Johnson and Johnson, other from Novartis, other from Boehringer Ingelheim, other from Astra Zeneca, other from GSK, grants from GSK, grants from Astra Zeneca, grants from Boehringer Ingelheim, grants from Novartis, outside the submitted work;.