title: Inhalation of LPS induces inflammatory airway responses mimicking characteristics of chronic obstructive pulmonary disease.
abstract: OBJECTIVE
  Inhalation of lipopolysaccharide (LPS) produces both systemic and pulmonary inflammatory responses. The aim of this study was to further characterize the response to LPS in order to develop a human model suitable for early testing of drug candidates developed for the treatment for chronic obstructive pulmonary disease (COPD).
  
  
  METHODS
  Blood and induced sputum were obtained 4, 24 and 48 h following inhalation of saline and LPS (5 and 50 μg). Blood was analysed for C-reactive protein (CRP), α(1)-antitrypsin and neutrophils/leucocytes, and sputum was analysed for biomarkers of neutrophil inflammation and remodelling activities, i.e. neutrophil elastase (NE) protein/activity and α(1)-antitrypsin. Levels of tumour necrosis factor-α (TNFα) were measured in both blood and sputum. Urine was collected 0-24 and 24-48 h postchallenge, and desmosine, a biomarker of elastin degradation, was measured.
  
  
  RESULTS
  Lipopolysaccharide inhalation induced dose-dependent flu-like symptoms and increases in plasma CRP and α(1)-antitrypsin as well as increases in blood neutrophil/leucocyte numbers. Furthermore, LPS produced increases in sputum TNFα and sputum NE activity. Urine levels of desmosine were unaffected by the LPS challenge. All subjects recovered 48 h postchallenge, and indices of inflammatory activity were significantly lower at this observation point cf 24 h postchallenge.
  
  
  CONCLUSIONS
  Inhalation of LPS in healthy volunteers can be used as a safe and stable model of neutrophil inflammation. Blood/plasma and sputum indices can be employed to monitor the response to LPS. We suggest that this model may be used for initial human studies of novel COPD-active drugs.
authors.affiliation: Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Korsgren
authors.forename: Margareta
authors.initials: M
authors.lastname: Linden
authors.forename: Neil
authors.initials: N
authors.lastname: Entwistle
authors.forename: Jason
authors.initials: J
authors.lastname: Cook
authors.forename: Per
authors.initials: P
authors.lastname: Wollmer
authors.forename: Morgan
authors.initials: M
authors.lastname: Andersson
authors.forename: Bengt
authors.initials: B
authors.lastname: Larsson
authors.forename: Lennart
authors.initials: L
authors.lastname: Greiff
mesh_terms: D000280:Administration, Inhalation; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D003895:Desmosine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005541:Forced Expiratory Volume; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D011014:Pneumonia / Q000097:blood / Q000139:chemically induced* / Q000276:immunology / Q000503:physiopathology / Q000652:urine; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000503:physiopathology; D013147:Spirometry; D013183:Sputum / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014797:Vital Capacity; D000515:alpha 1-Antitrypsin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D008070:Lipopolysaccharides; C043392:SERPINA1 protein, human; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; C433788:lipopolysaccharide, E. coli O26-B6; D003895:Desmosine; D002097:C-Reactive Protein; D019272:Leukocyte Elastase