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Open Access Research article

Low-dose endotoxin inhalation in healthy volunteers - a challenge model for early clinical drug development

Ole Janssen12, Frank Schaumann1, Olaf Holz14*, Bianca Lavae-Mokhtari12, Lutz Welker3, Carla Winkler12, Heike Biller1, Norbert Krug14 and Jens M Hohlfeld124

Author Affiliations

1 Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany

2 Hannover Medical School (MHH), Hannover, Germany

3 LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research, Großhansdorf, Germany

4 Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research, Hannover, Germany

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BMC Pulmonary Medicine 2013, 13:19  doi:10.1186/1471-2466-13-19

Published: 28 March 2013

Abstract

Background

Inhalation of endotoxin (LPS) induces a predominantly neutrophilic airway inflammation and has been used as model to test the anti-inflammatory activity of novel drugs. In the past, a dose exceeding 15–50 μg was generally needed to induce a sufficient inflammatory response. For human studies, regulatory authorities in some countries now request the use of GMP-grade LPS, which is of limited availability. It was therefore the aim of this study to test the effect and reproducibility of a low-dose LPS challenge (20,000 E.U.; 2 μg) using a flow- and volume-controlled inhalation technique to increase LPS deposition.

Methods

Two to four weeks after a baseline sputum induction, 12 non-smoking healthy volunteers inhaled LPS on three occasions, separated by at least 4 weeks. To modulate the inflammatory effect of LPS, a 5-day PDE4 inhibitor (Roflumilast) treatment preceded the last challenge. Six hours after each LPS inhalation, sputum induction was performed.

Results

The low-dose LPS inhalation was well tolerated and increased the mean percentage of sputum neutrophils from 25% to 72%. After the second LPS challenge, 62% neutrophils and an increased percentage of monocytes were observed. The LPS induced influx of neutrophils and the cumulative inflammatory response compared with baseline were reproducible. Treatment with Roflumilast for 5 days did not have a significant effect on sputum composition.

Conclusion

The controlled inhalation of 2 μg GMP-grade LPS is sufficient to induce a significant neutrophilic airway inflammation in healthy volunteers. Repeated low-dose LPS challenges potentially result in a small shift of the neutrophil/monocyte ratio; however, the cumulative response is reproducible, enabling the use of this model for “proof-of-concept” studies for anti-inflammatory compounds during early drug development.

Trial registration

Clinicaltrials.gov: NCT01400568

Keywords:
Induced sputum; Airway inflammation; Reproducibility; Sputum flow cytometry; Sputum monocytes