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Ex vivo lung culture models of marmoset monkeys and humans for anti-inflammatory drug testing

 
: Seehase, Sophie; Neuhaus, Vanessa; Kaup, Franz-Josef; Pfennig, O.; Förster, Christine; Hohlfeld, Jens Michael; Knauf, Sascha; Braun, Armin; Sewald, Katherina

American Journal of Respiratory and Critical Care Medicine 185 (2012), Abstract A4169
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2012, San Francisco/Calif.>
English
Abstract
Fraunhofer ITEM ()

Abstract
Introduction: There is growing burden of chronic obstructive pulmonary diseases (COPD). Currently available treatments have, however, only minimal impact on disease progression. Thus, new pre-clinical in vitro / ex vivo animal models which closely reflect anatomy and organ physiology of the human respiratory tract are needed to enhance therapeutic approaches. Here we display inflammatory aspects of COPD in a lipopolysaccharide (LPS) induced acute inflammation in vitro model in marmoset monkeys (Callithrix jacchus) and humans.
Methods: Peripheral blood and precision cut lung slices (PCLS) of marmoset monkeys and healthy human subjects were incubated with LPS for 24 hrs. The inflammatory response was modulated with roflumilast and dexamethasone. Supernatants were analysed for TNF-a by ELISA. The results for marmosets were correlated with the human data.
Results: Peripheral blood and PCLS showed a dose-dependent a response to LPS. The TNF-a response in marmoset peripheral blood correlated significantly with the TNF-a response in marmoset PCLS (r²=0.96, p=0.0007). This was also true for human. The correlation of the ex vivo cytokine response between both species was also high in PCLS (r²=0.89). Anti-inflammatory treatment with roflumilast and dexamethasone suppressed LPS-induced TNF-a in lung tissue. Roflumilast reduced TNF-a to e.g. 61 % in marmoset and 66 % in human.
The were calculated to be about 1.6 nM and 1.3 nM for marmoset and humans, respectively. Dexamethasone was also efficient. Here, the marked reduction of cytokine response was also used to calculate the IC50 which was about 0.4 nM (marmoset) and 8.4 pM (human).
Discussion: There is a high analogy in the lung specific cytokine response of humans and marmosets as seen by the great similarities concerning LPS-induced inflammation in both species. Moreover, for marmoset monkeys the peripheral blood cytokine response is very similar to the lung specific cytokine response. Dexamethasone and roflumilast were effective in suppressing inflammatory responses in peripheral blood and PCLS of both species.
Conclusion: In vitro models of marmoset monkeys are a promising preclinical model to study human inflammatory diseases.

: http://publica.fraunhofer.de/documents/N-226382.html