Inhibition of LPS-induced airway neutrophilic inflammation in healthy volunteers with an oral CXCR2 antagonist

Respiratory Research

Brian O’Connor²  Peter J Barnes¹  Brian R Leaker² 

[1] National Heart & Lung Institute, Imperial College, London SW3 6LY, UK;Respiratory Clinical Trials Ltd, 20 Queen Anne Street, London W1G 8HU, UK

关键词: Endotoxin;    Cystic fibrosis;    Severe asthma;    COPD;    CXCL1;    Chemokine receptor;    Neutrophil;   

Others  :  792209
DOI  :  10.1186/1465-9921-14-137

 received in 2013-08-28, accepted in 2013-11-12,  发布年份 2013

【 摘 要 】

Background

Inhaled lipopolysaccharide (LPS) induces a dose-dependent, acute neutrophilic response in the airways of healthy volunteers that can be quantified in induced sputum. Chemokines, such as CXCL1 and CXCL8, play an important role in neutrophilic inflammation in the lung through the activation of CXCR2 and small molecule antagonists of these receptors have now been developed. We investigated the effect of AZD8309, a CXCR2 antagonist, compared with placebo on LPS-induced inflammation measured in sputum of healthy volunteers.

Methods

Twenty healthy subjects were randomized in a double-blind placebo-controlled, cross-over study. AZD8309 (300 mg) or placebo was dosed twice daily orally for 3 days prior to challenge with inhaled LPS and induced sputum was collected 6 h later.

Results

Treatment with AZD8309 showed a mean 77% reduction in total sputum cells (p < 0.001) and 79% reduction in sputum neutrophils (p < 0.05) compared with placebo after LPS challenge. There was also a reduction in neutrophil elastase activity (p < 0.05) and CXCL1 (p < 0.05) and trends for reductions in sputum macrophages (47%), leukotriene B₄ (39%) and CXCL8 (52%).

Conclusions

AZD8309 inhibited LPS-induced inflammation measured in induced sputum of normal volunteers, indicating that this treatment may be useful in the treatment of neutrophilic diseases of the airways, such as COPD, severe asthma and cystic fibrosis.

Trial registration

NCT00860821.

【 授权许可】

   
2013 Leaker et al.; licensee BioMed Central Ltd.

【 图 表 】

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