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

: Janssen, Ole; Schaumann, Frank; Holz, Olaf; Lavae-Mokhtari, Bianca; Welker, Lutz; Winkler, Carla; Biller, Heike; Krug, Norbert; Hohlfeld, Jens M.

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BMC Pulmonary Medicine. Online journal 13 (2013), Art. 19, 11 pp.
ISSN: 1471-2466
Journal Article, Electronic Publication
Fraunhofer ITEM ()
induced sputum; airway inflammation; reproducibility; sputum flow cytometry; sputum monocytes

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 g 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 g) 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 g 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: NCT01400568.