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LPS-induced lung inflammation in marmoset monkeys - an acute model for anti-inflammatory drug testing

: Seehase, S.; Lauenstein, H.D.; Schlumbohm, C.; Switalla, S.; Neuhaus, V.; Förster, C.; Fieguth, H.G.; Pfennig, O.; Fuchs, E.; Kaup, F.J.; Bleyer, M.; Hohlfeld, J.M.; Braun, A.; Sewald, K.; Knauf, S.

Fulltext urn:nbn:de:0011-n-2233620 (592 KByte PDF)
MD5 Fingerprint: 1fe8447aed03191f462cd8a621211ad5
Created on: 18.1.2013

PLoS one. Online journal 7 (2012), No.8, Art.e43709, 11 pp.
ISSN: 1932-6203
Journal Article, Electronic Publication
Fraunhofer ITEM ()

Increasing incidence and substantial morbidity and mortality of respiratory diseases requires the development of new human-specific anti-inflammatory and disease-modifying therapeutics. Therefore, new predictive animal models that closely reflect human lung pathology are needed. In the current study, a tiered acute lipopolysaccharide (LPS)-induced inflammation model was established in marmoset monkeys (Callithrix jacchus) to reflect crucial features of inflammatory lung diseases. Firstly, in an ex vivo approach marmoset and, for the purposes of comparison, human precision-cut lung slices (PCLS) were stimulated with LPS in the presence or absence of the phosphodiesterase-4 (PDE4) inhibitor roflumilast. Pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-1 beta (MIP-1 beta) were measured. The corticosteroid dexamethasone was used as treatment control. Secondly, in an in vivo approach marmosets were pre-treated with roflumilast or dexamethasone and unilaterally challenged with LPS. Ipsilateral bronchoalveolar lavage (BAL) was conducted 18 hours after LPS challenge. BAL fluid was processed and analyzed for neutrophils, TNF-alpha, and MIP-1 beta. TNF-alpha release in marmoset PCLS correlated significantly with human PCLS. Roflumilast treatment significantly reduced TNF-alpha secretion ex vivo in both species, with comparable half maximal inhibitory concentration (IC50). LPS instillation into marmoset lungs caused a profound inflammation as shown by neutrophilic influx and increased TNF-alpha and MIP-1 beta levels in BAL fluid. This inflammatory response was significantly suppressed by roflumilast and dexamethasone. The close similarity of marmoset and human lungs regarding LPS-induced inflammation and the significant anti-inflammatory effect of approved pharmaceuticals assess the suitability of marmoset monkeys to serve as a promising model for studying anti-inflammatory drugs.