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Am J Respir Crit Care Med. 2017 Oct 1;196(7):845-855. doi: 10.1164/rccm.201608-1714OC.

Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages.

Author information

1
1 The Florey Institute for Host-Pathogen Interactions and.
2
2 Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom.
3
3 Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.
4
4 Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
5
5 Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
6
6 Instiute for Lung Heath, University of Leicester, Leicester, United Kingdom.
7
7 Airway Disease National Heart and Lung Institute, Imperial College London, London, United Kingdom.
8
8 Centre for Respiratory and Allergy, University of Manchester, Manchester, United Kingdom.
9
9 Medicines Evaluation Unit, Manchester, United Kingdom.
10
10 University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
11
11 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and.
12
12 Department of Respiratory Medicine.
13
13 MRC Centre for Inflammation Research, and.
14
14 Department of Infection Medicine, University of Edinburgh, Edinburgh, United Kingdom.

Abstract

RATIONALE:

Chronic obstructive pulmonary disease (COPD) is characterized by impaired clearance of pulmonary bacteria.

OBJECTIVES:

The effect of COPD on alveolar macrophage (AM) microbicidal responses was investigated.

METHODS:

AMs were obtained from bronchoalveolar lavage from healthy donors or patients with COPD and challenged with opsonized serotype 14 Streptococcus pneumoniae. Cells were assessed for apoptosis, bactericidal activity, and mitochondrial reactive oxygen species (mROS) production. A transgenic mouse line in which the CD68 promoter ensures macrophage-specific expression of human induced myeloid leukemia cell differentiation protein Mcl-1 (CD68.hMcl-1) was used to model the molecular aspects of COPD.

MEASUREMENTS AND MAIN RESULTS:

COPD AMs had elevated levels of Mcl-1, an antiapoptotic B-cell lymphoma 2 family member, with selective reduction of delayed intracellular bacterial killing. CD68.hMcl-1 AMs phenocopied the microbicidal defect because transgenic mice demonstrated impaired clearance of pulmonary bacteria and increased neutrophilic inflammation. Murine bone marrow-derived macrophages and human monocyte-derived macrophages generated mROS in response to pneumococci, which colocalized with bacteria and phagolysosomes to enhance bacterial killing. The Mcl-1 transgene increased oxygen consumption rates and mROS expression in mock-infected bone marrow-derived macrophages but reduced caspase-dependent mROS production after pneumococcal challenge. COPD AMs also increased basal mROS expression, but they failed to increase production after pneumococcal challenge, in keeping with reduced intracellular bacterial killing. The defect in COPD AM intracellular killing was associated with a reduced ratio of mROS/superoxide dismutase 2.

CONCLUSIONS:

Up-regulation of Mcl-1 and chronic adaption to oxidative stress alter mitochondrial metabolism and microbicidal function, reducing the delayed phase of intracellular bacterial clearance in COPD.

KEYWORDS:

Streptococcus pneumoniae; apoptosis; mitochondrial reactive oxygen species

Comment in

PMID:
28557543
PMCID:
PMC5649972
DOI:
10.1164/rccm.201608-1714OC
[Indexed for MEDLINE]
Free PMC Article

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