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Impaired mitochondrial microbicidal responses in chronic obstructive pulmonary disease macrophages

Research output: Contribution to journalArticlepeer-review

  • Martin A. Bewley
  • Julie A. Preston
  • Mohammed Mohasin
  • Helen M. Marriott
  • Richard C Budd
  • Julie Swales
  • Paul Collini
  • David R Greaves
  • Ruth W Craig
  • Christopher E Brightling
  • Louise E Donnelly
  • Peter J Barnes
  • David Singh
  • Steven D Shapiro
  • Moira K. B. Whyte
  • David H. Dockrell

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Original languageEnglish
Pages (from-to)845–855
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume196
Issue number7
Early online date30 May 2017
DOIs
Publication statusPublished - 1 Oct 2017

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.

    Research areas

  • apoptosis, mitochondrial reactive oxygen species, Streptococcus pneumoniae

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