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Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease is Enhanced by Nrf2 Agonists

Research output: Contribution to journalArticle

  • Martin A Bewley
  • Richard C Budd
  • Eilise Ryan
  • Joby Cole
  • Paul Collini
  • Jennifer Marshall
  • Umme Kolsum
  • Gussie Beech
  • Richard D Emes
  • Irina Tcherniaeva
  • Guy A M Berbers
  • Sarah R. Walmsley
  • Gavin Donaldson
  • Jadwiga A Wedzicha
  • Iain Kilty
  • William Rumsey
  • Yolanda Sanchez
  • Christopher E Brightling
  • Louise E Donnelly
  • Peter J Barnes
  • Dave Singh
  • Moira K. B. Whyte
  • David H. Dockrell
  • COPDMAP

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Original languageEnglish
Pages (from-to)739-750
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume198
Issue number6
Early online date16 Mar 2018
DOIs
Publication statusPublished - 15 Sep 2018

Abstract

Rationale: Previous studies have identified defects in bacterial phagocytosis by alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms and clinical consequences remain incompletely defined.

Objectives: To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences, and potential for therapeutic manipulation of these defects.

Methods: We isolated AMs and monocyte-derived macrophages (MDMs) from a cohort of patients with COPD and control subjects within the Medical Research Council COPDMAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features.

Measurements and Main Results: COPD AMs and MDMs have impaired phagocytosis of Streptococcus pneumoniae. COPD AMs have a selective defect in uptake of opsonized bacteria, despite the presence of antipneumococcal antibodies in BAL, not observed in MDMs or healthy donor AMs. AM defects in phagocytosis in COPD are significantly associated with exacerbation frequency, isolation of pathogenic bacteria, and health-related quality-of-life scores. Bacterial binding and initial intracellular killing of opsonized bacteria in COPD AMs was not reduced. COPD AMs have reduced transcriptional responses to opsonized bacteria, such as cellular stress responses that include transcriptional modules involving antioxidant defenses and Nrf2 (nuclear factor erythroid 2–related factor 2)-regulated genes. Agonists of the cytoprotective transcription factor Nrf2 (sulforaphane and compound 7) reverse defects in phagocytosis of S. pneumoniae and nontypeable Haemophilus influenzae by COPD AMs.

Conclusions: Patients with COPD have clinically relevant defects in opsonic phagocytosis by AMs, associated with impaired transcriptional responses to cellular stress, which are reversed by therapeutic targeting with Nrf2 agonists.

    Research areas

  • Journal Article, chronic obstructuve pulmonary disease, macrophage, phagocytosis, antioxidant, nuclear factor erythoid 2-related factor 2(Nrf2)

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