title: Inhaled LPS challenges in smokers: a study of pulmonary and systemic effects.
abstract: OBJECTIVE
  Lipopolysaccharide (LPS) is a TLR4 agonist which activates NFκB dependent cytokine production. We investigated LPS inhalation in healthy smokers as a model of COPD bacterial exacerbations. We studied safety, reproducibility, the translocation of the NFκB subunit p65 in sputum cells and changes in systemic biomarkers of inflammation.
  
  
  METHODS
  Twelve smokers inhaled 5 and 30 µg LPS and safety was monitored over 24 h. IL-6, CRP, CCl-18, SP-D, CC-16 and β-defensin 2 were measured in serum samples collected at baseline, 4, 8 and 24 h. Sputum was induced at baseline, 6 and 24 h for cell counts and p65 expression. Repeated challenges were performed after a 2 week interval in 10 smokers.
  
  
  RESULTS
  LPS inhalation was well tolerated. Significant increases occurred in sputum neutrophil counts with both doses, with a maximum increase of 21.5% at 6 h after 30 µg which was reproducible, r(i ) (intraclass correlation coefficient) = 0.88. LPS increased sputum cell nuclear p65 translocation and phospho-p65 expression. All of the serum biomarkers increased following challenge but with different temporal patterns.
  
  
  CONCLUSIONS
  Inhaled LPS challenge in smokers causes pulmonary and systemic inflammation that involves NFκB activation. This appears to be a suitable model for studying bacterial exacerbations of COPD.
authors.affiliation: University of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester, Manchester, UK.
authors.forename: Raminder
authors.initials: R
authors.lastname: Aul
authors.forename: Jane
authors.initials: J
authors.lastname: Armstrong
authors.forename: Annelyse
authors.initials: A
authors.lastname: Duvoix
authors.forename: David
authors.initials: D
authors.lastname: Lomas
authors.forename: Brian
authors.initials: B
authors.lastname: Hayes
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Miller
authors.forename: Chris
authors.initials: C
authors.lastname: Jagger
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
mesh_terms: D000280:Administration, Inhalation; D015415:Biomarkers / Q000378:metabolism; D019742:Chemokines, CC / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D019570:Inhalation Exposure; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008168:Lung / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000139:chemically induced*; D037663:Pulmonary Surfactant-Associated Protein D / Q000097:blood; D012907:Smoking; D013183:Sputum / Q000276:immunology*; D051996:Transcription Factor RelA / Q000097:blood; D014598:Uteroglobin / Q000097:blood; D023083:beta-Defensins / Q000097:blood
chemical_list: D015415:Biomarkers; C111792:CCL18 protein, human; D019742:Chemokines, CC; C106641:DEFB4A protein, human; D008070:Lipopolysaccharides; D037663:Pulmonary Surfactant-Associated Protein D; C556389:SCGB1A1 protein, human; D051996:Transcription Factor RelA; D023083:beta-Defensins; C433788:lipopolysaccharide, E. coli O26-B6; D014598:Uteroglobin