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Thorax 69:811-818 doi:10.1136/thoraxjnl-2013-203669
  • Chronic obstructive pulmonary disease
  • Original article

Impaired innate immune alveolar macrophage response and the predilection for COPD exacerbations

  1. Sanjay Sethi2
  1. 1Infectious Disease Division, Department of Veterans Affairs Western New York Healthcare System, State University of New York at Buffalo School of Medicine, Buffalo, New York, USA
  2. 2Pulmonary, Critical Care and Sleep Division, Department of Veterans Affairs Western New York Healthcare System, State University of New York at Buffalo School of Medicine, Buffalo, New York, USA
  3. 3Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, New York, USA
  1. Correspondence to Dr Charles S Berenson, Division of Infectious Diseases (151), VA Western NY Healthcare System, 3495 Bailey Avenue, Buffalo, NY 14215, USA; berenson{at}buffalo.edu
  • Received 1 April 2013
  • Revised 24 February 2014
  • Accepted 27 February 2014
  • Published Online First 31 March 2014

Abstract

Background Alveolar macrophages (AM) in COPD have fundamentally impaired responsiveness to Toll-like receptor 2 (TLR2) and TLR4 ligands of non-typeable Haemophilus influenzae (NTHI). However, the contribution of innate immune dysfunction to exacerbations of COPD is unexplored. We hypothesised that impaired innate AM responses in COPD extend beyond NTHI to other pathogens and are linked with COPD exacerbations and severity.

Methods AMs, obtained by bronchoalveolar lavage from 88 volunteers with stable-to-moderate COPD, were incubated with respiratory pathogens (NTHI, Moraxella catarrhalis (MC), Streptococcus pneumoniae (SP) and TLR ligands lipopolysaccharide, Pam3Cys) and elicited IL-8 and TNF-α were measured by microsphere flow cytometry. NF-κB nuclear translocation was measured by colorimetric assay. AM TLR2 and TLR4 expression was determined by immunolabeling and quantitation of mean fluorescent indices. Participants were monitored prospectively for occurrence of COPD exacerbations for 1 year following bronchoscopy. Non--parametric analyses were used to compare exacerbation-prone and non-exacerbation-prone individuals.

Results 29 subjects had at least one exacerbation in the follow-up period (exacerbation-prone) and 59 remained exacerbation-free (non-exacerbation-prone). AMs of exacerbation-prone COPD donors were more refractory to cytokine induction by NTHI (p=0.02), MC (p=0.045) and SP (p=0.046), and to TLR2 (p=0.07) and TLR4 (p=0.028) ligands, and had diminished NF-κB nuclear activation, compared with non-exacerbation-prone counterparts. AMs of exacerbation-prone subjects were more refractory to TLR2 upregulation by MC and SP (p=0.04 each).

Conclusions Our results support a paradigm of impaired innate responses of COPD AMs to respiratory pathogens, mediated by impaired TLR responses, underlying a propensity for exacerbations in COPD.