Inhaled LPS challenges in smokers: a study of pulmonary and systemic effects

Authors


Professor Dave Singh, University of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester, Manchester M23 9LT, UK. Tel.: +0161 946 4073. Fax: +0161 946 1459. E-mail: dsingh@meu.org.uk

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Neutrophilic airway inflammation is a feature of chronic obstructive pulmonary disease (COPD). Inhaled lipopolysaccharide (LPS) challenge in healthy non-smokers has been used to assess the anti-inflammatory effects of novel drugs on neutrophilic airway inflammation.

WHAT THIS STUDY ADDS

• We performed inhaled LPS challenge in smokers to study an inflammatory response in subjects who more closely resemble COPD patients. Inhaled LPS caused reproducible pulmonary inflammation in smokers, associated with changes in systemic biomarkers. Inhaled LPS appears to be a suitable model for studying exacerbations of COPD.

AIMS 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, ri (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.

DISCUSSION 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.

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