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Airway inflammation evaluated in a human nasal lipopolysaccharide challenge model by investigating the effect of a CXCR 2 inhibitor
Author(s) -
Virtala R.,
Ekman A.K.,
Jansson L.,
Westin U.,
Cardell L. O.
Publication year - 2012
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/j.1365-2222.2011.03921.x
Subject(s) - medicine , placebo , nasal lavage , inflammation , neutrophil elastase , immunology , lipopolysaccharide , nose , nasal administration , sputum , nostril , bronchoalveolar lavage , adverse effect , allergy , pathology , surgery , lung , tuberculosis , alternative medicine
Summary 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 CXCR 2 inhibitor AZD 8309 on neutrophilic inflammation. Methods A total of 18 healthy volunteers were randomized in a placebo‐controlled, double‐blind, cross‐over study. AZD 8309 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 C urrent C ontrolled T rials register ( ISRCTN trial number: ISRCTN 46666382). Results The leucocytes in nasal lavage consisted to 99% of neutrophils on average. Treatment with AZD 8309 reduced the leucocyte count to 48% of placebo 6 h after the LPS challenge. There was also a reduction in LTB 4 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 AZD 8309 or placebo. The nasal LPS model induced only minimal local irritation and no signs of systemic inflammation. Conclusions and Clinical Relevance LPS ‐induced neutrophil recruitment was reduced by inhibition of CXCR 2. 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.