title: Impaired innate immune alveolar macrophage response and the predilection for COPD exacerbations.
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.
authors.affiliation: Infectious 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.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Berenson
authors.affiliation: Infectious 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.
authors.forename: Ragina L
authors.initials: RL
authors.lastname: Kruzel
authors.affiliation: Pulmonary, 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.
authors.forename: Ellana
authors.initials: E
authors.lastname: Eberhardt
authors.affiliation: Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Ree
authors.initials: R
authors.lastname: Dolnick
authors.affiliation: Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Hans
authors.initials: H
authors.lastname: Minderman
authors.affiliation: Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Wallace
authors.affiliation: Pulmonary, 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.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sethi
mesh_terms: D002478:Cells, Cultured; D018920:Coculture Techniques; D018450:Disease Progression; D005260:Female; D006193:Haemophilus influenzae / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides; D008074:Lipoproteins / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D001936:Moraxella catarrhalis / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016209:Interleukin-8; D008024:Ligands; D008070:Lipopolysaccharides; D008074:Lipoproteins; D016328:NF-kappa B; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine
keywords: COPD Exacerbations; Cytokine Biology; Innate Immunity; Macrophage Biology