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Reproducibility of serum biomarkers and relationship to airway inflammation following LPS challenge in healthy volunteers

: Holz, Olaf; Tan, Lisa; Faulenbach, Cornelia; Müller, Meike; Krug, Norbert; McLeod, Alison; Hohlfeld, Jens M.

American Journal of Respiratory and Critical Care Medicine 185 (2012), Abstract A3937
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2012, San Francisco/Calif.>
Fraunhofer ITEM ()

Rationale: Segmental endotoxin (LPS) challenge induces neutrophilic airway inflammation in healthy subjects. It allows the precise administration of LPS to a specific lung region and the use of a vehicle challenged segment within the same individual as a control. When compared to whole lung LPS challenge, it targets more peripheral lung regions, requires only a fraction of the LPS dose and has been shown to respond to treatment with a PDE4 inhibitor (Hohlfeld et al. PPT 2008). We assessed the reproducibility of systemic biomarkers in response to local pulmonary LPS challenge and analysed the relationship of serum biomarkers assessed at seven different time points after LPS challenge with the extent of neutrophilic airway inflammation detected 6 and 24 hours following the LPS challenge.
Methods: Two cohorts with 10 subjects each underwent 2 segmental LPS challenges within 4 weeks. The inflammatory response was evaluated in BAL fluid at 6 (cohort 1) and 24 hours (cohort 2) both in the LPS and in the saline challenged segments, as well as in serum prior to and at 1, 3, 5.5, 8, 10, 23.5 and 26 hours post LPS challenge.
Results: For the baseline values (prior to LPS challenge) the correlation coefficients (n=20 subjects) for the comparison between visits were >0.8 for CC16, MIP1ß, MPO, SP-D, 0.73 for lactoferrin and 0.68 for TNF-. A repeatable increase in serum concentration up to 5.5h following LPS challenge compared to baseline was observed for CC16 (1, 3, 5.5h), IL-6 (5.5h), lactoferrin (5.5h), MCP-1 (5.5h), MIP1ß (3, 5.5 h) and TNF- (5.5 h) (repeated measures ANOVA). No significant correlations were observed between 6 h or the 24 h BAL neutrophil counts and serum collected at the different time points.
Conclusion: Serum CC16, IL-6, lactoferrin, MCP-1, and MIP1ß show a repeatable response to segmental LPS challenge, but individual serum biomarkers were not related to the cellular inflammatory response observed in BAL after LPS challenge. Despite reproducibility, serum biomarker assessment following segmental LPS challenge seem to be of limited added value to monitor the local pulmonary response.