title: Airway inflammation evaluated in a human nasal lipopolysaccharide challenge model by investigating the effect of a CXCR2 inhibitor.
abstract: BACKGROUND
  The existence of a link between inflammation in upper and lower airways is well established. It may therefore be assumed that the nose could be used to study inflammatory events in the lower airways.
  
  
  OBJECTIVE
  This study aimed to evaluate a lipopolysaccharide (LPS) nasal challenge model by investigating the effect of the CXCR2 inhibitor AZD8309 on neutrophilic inflammation.
  
  
  METHODS
  A total of 18 healthy volunteers were randomized in a placebo-controlled, double-blind, cross-over study. AZD8309 or placebo was dosed for 3 days. Subjects were challenged nasally with LPS (50 μg/nostril), and nasal lavage was performed 6 and 24 h later. Leucocytes, neutrophils and inflammatory mediators were assessed in the lavage fluid. The outcome was compared with data from analogous experiments performed in a model of inhaled LPS followed by induced sputum. This trial was registered in the Current Controlled Trials register (ISRCTN trial number: ISRCTN46666382).
  
  
  RESULTS
  The leucocytes in nasal lavage consisted to 99% of neutrophils on average. Treatment with AZD8309 reduced the leucocyte count to 48% of placebo 6 h after the LPS challenge. There was also a reduction in LTB4 levels to 45% of placebo after 6 h and in the neutrophil elastase activity after 24 h. No major adverse events were seen with either AZD8309 or placebo. The nasal LPS model induced only minimal local irritation and no signs of systemic inflammation.
  
  
  CONCLUSIONS
  LPS-induced neutrophil recruitment was reduced by inhibition of CXCR2. This outcome mimicked the response previously seen in a lower airway LPS model. Hence, the nasal model offers a convenient and well-tolerated alternative for pharmacological evaluation of anti-inflammatory drugs affecting neutrophilic migration and activity.
authors.affiliation: Astra Zeneca R&D, Lund, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Virtala
authors.forename: A-K
authors.initials: AK
authors.lastname: Ekman
authors.forename: L
authors.initials: L
authors.lastname: Jansson
authors.forename: U
authors.initials: U
authors.lastname: Westin
authors.forename: L O
authors.initials: LO
authors.lastname: Cardell
mesh_terms: D018592:Cross-Over Studies; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000276:immunology*; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000276:immunology*; D008168:Lung / Q000276:immunology; D017817:Nasal Lavage Fluid / Q000737:chemistry / Q000276:immunology; D009297:Nasal Mucosa / Q000187:drug effects* / Q000276:immunology*; D009299:Nasal Provocation Tests / Q000379:methods*; D020556:Neutrophil Infiltration / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors
chemical_list: C573077:AZD8309; D008070:Lipopolysaccharides; D011743:Pyrimidines; D023063:Receptors, Interleukin-8B