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Low-dose endotoxin inhalation in healthy volunteers: A challenge model for early clinical drug development of novel anti-inflammatory compounds

: Schaumann, Frank; Holz, Olaf; Janben, Ole; Lavae-Mokhtari, Bianca; Witte, Lena; Biller, Heike; Krug, Norbert; Hohlfeld, Jens M.

American Journal of Respiratory and Critical Care Medicine 185 (2012), Abstract A4318
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2012, San Francisco/Calif.>
Fraunhofer ITEM ()

Introduction: Inhaled endotoxin can be used as a challenge model to study inflammatory processes within the airways. Substantial amounts of endotoxin (15 - 50 µg) were used in the past to elicit a neutrophilic airway inflammation by conventional inhalation. In contrast, controlled inhalation can largely increase deposition. Because regulatory requirements in many countries request GMP-grade endotoxin which is of limited availability, controlled inhalation with low doses of endotoxin might allow to overcome this shortage. Therefore, the aim of this study was to investigate whether a low-dose endotoxin inhalation results in a sufficient neutrophilic airway inflammation.
Methodology: Twelve healthy volunteers (non-smokers, mean (SD) age: 38±11, FEV1: 104.2±7.3 % pred.) were included in the study. The volunteers inhaled 2 µg lipopolysaccharide (LPS, Clinical Center Reference Endotoxin, NIH Bethesda, USA), which was nebulized during standardized inhalations using an Aeroneb solo (Inspiration Medical). Sputum was induced 6 hours after endotoxin provocation and the cellular composition was compared to the baseline value (screening visit 2-4 weeks prior to the challenge visit). The exhaled breath temperature was measured with the x-Halo thermometer (Delmedica).
Results: The LPS inhalation was well tolerated with no adverse effects. There was a small but significant (p=0.005) transient change in lung function 1h after LPS inhalation (median (IQR) 95.9 (90.8, 100) % of pre-challenge value). Exhaled breath temperature and body temperature were increased 6 hours post challenge (ANOVA p=0.054, p 0.001). The percentage of neutrophilic granulocytes in sputum increased from 23.6 (8.6; 38.2) % at baseline to 69.4 (59.6; 78.4) % after endotoxin provocation (p=0,003). Furthermore, an increase in monocytes (p=0,01) and total cell numbers per ml sputum (p=0,002) was observed.
Conclusion: Low-dose endotoxin inhalation is sufficient to induce a significant influx of neutrophils and monocytes into the airways. In the second part of this study the reproducibility of this effect will be assessed to validate this model for proof of concept studies in the early development of novel anti-inflammatory compounds.
Clinical Center Reference Endotoxin was kindly provided by Dr. A. Suffredini, NIH Clinical Center, Bethesda, MD