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Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD

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Selasa, 22 Okt 2019 11:44:47

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 on behalf of the COPD-MAP consortium

European Respiratory Journal 2019 54: 1802244; DOI: 10.1183/13993003.02244-2018

Abstract

Increased reactive oxygen species ROS have been implicated in the pathophysiology of chronic obstructive pulmonary disease COPD. This study examined the effect of exogenous and endogenous oxidative stress on macrophage phagocytosis in patients with COPD.

Monocyte derived macrophages MDMs were generated from non-smoker, smoker and COPD subjects, differentiated in either granulocyte macrophage colony stimulating factor or macrophage-colony stimulating factor. Alveolar macrophages were isolated from lung tissue or bronchoalveolar lavage fluid. Macrophages were incubated in rather than 200 M H2O2 for 24 h, then exposed to fluorescently labelled Haemophilus influenzae or Streptococcus pneumoniae for 4 h, after which phagocytosis, mitochondrial ROS mROS and mitochondrial membrane potential were measured.

Phagocytosis of bacteria was significantly decreased in both G-M and M-Mo from COPD patients compared with from non-smoker controls. In non-smokers and smokers, bacterial phagocytosis did not alter mROS or Am however, in COPD, phagocytosis increased early mROS and decreased Am in both G-Mo and M-Mo. Exogenous oxidative stress reduced phagocytosis in non-smoker and COPD alveolar macrophages and non-smoker MDMs, associated with reduced mROS production.

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.

Footnotes

Author contributions: Conception and design: K.B.R. Belchamber, L.E. Donnelly, P.J. Barnes, J.A. Wedzicha, M.K. Whyte, D.H. Dockrell, I. Kilty and M.J. Robinson. Acquisition of samples: K.B.R. Belchamber, C.M. Batista, R. Singh and J.A. Wedzicha. Performance of experiments: K.B.R. Belchamber and C.M. Batista. Analysis and interpretation of data: K.B.R. Belchamber and L.E. Donnelly. Manuscript preparation: K.B.R. Belchamber and L.E. Donnelly. All authors approved the final manuscript.
Conflict of interest: K.B.R. Belchamber reports grants from MRC during the conduct of the study.
Conflict of interest: R. Singh has nothing to disclose.
Conflict of interest: C.M. Batista reports grants from the National Institute for Health Research during the conduct of the study; and reports grants from Cempra Pharmaceuticals, lecture fees and educational presentations, outside the submitted work.
Conflict of interest: M.K. Whyte reports grants from MRC during the conduct of the study; and reports grants for travel from Boehringer Ingelheim, outside the submitted work.
Conflict of interest: D.H. Dockrell reports grants from MRC and Wellcome Trust during the conduct of the study; and grants from GSK, advisory board membership for Lilly and ViiV, non-financial support from Novartis, and other funding from AstraZeneca, MedImmune, RedX Pharmaceuticals, Sygnature Discovery, Pfizer and GSK, outside the submitted work.
Conflict of interest: I. Kilty is an employee of Pfizer and holds stocks in Pfizer.
Conflict of interest: M.J. Robinson is an employee of MedImmune and holds stocks in MedImmune.
Conflict of interest: J.A. Wedzicha reports grants from GSK and Johnson and Johnson, other funding from Novartis, Boehringer Ingelheim, AstraZeneca and GSK, and grants from GSK, AstraZeneca, Boehringer Ingelheim and Novartis, outside the submitted work.
Conflict of interest: P.J. Barnes has nothing to disclose.
Conflict of interest: L.E. Donnelly reports grants from MRC during the conduct of the study; and has grants pending from Cempra Inc., AstraZeneca and Boehringer Ingelheim, outside the submitted work.
Support statement: This study was funded by the Medical Research Council MRC and the Association of the British Pharmaceutical Industry ABPI though support for the MRC-ABPI COPD-MAP consortium G1001367/1. This study was supported by the National Institute for Health Research NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. Funding information for this article has been deposited with the Crossref Funder Registry.