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A new model for testing human specific anti-inflammatory drugs: LPS-induced lung inflammation in the common marmoset

: Knauf, Sascha; Seehase, Sophie; Switalla, Simone; Neuhaus, Vanessa; Zöller, Martina; Kaup, Franz-Josef; Schlumbohm, Christina; Fuchs, Eberhard; Lauenstein, Hand D.; Sewald, Katherina; Hohlfeld, Jens Michael; Braun, Armin

American Journal of Respiratory and Critical Care Medicine 185 (2012), Abstract A5697
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2012, San Francisco/Calif.>
Fraunhofer ITEM ()

The rising incidence and morbidity of chronic obstructive pulmonary diseases (COPD) is linked to the development of new human-specific anti-inflammatory and disease modifying therapeutics. New animal models that closely reflect anatomy and physiology of the human respiratory tract are needed for pre-testing and evaluation of potential human specific drug candidates. An acute lipopolysaccharide (LPS) induced lung inflammation model similar to the human setting of segmental LPS challenge was established in the common marmoset (Callithrix jacchus), a small non-human primate, to mimic pro-inflammatory aspects of COPD. Only animals that matched our health criteria in clinical examination, hematology, blood-chemistry, bronchoalveolar lavage (BAL) and whole blood assay (WBA) were included into the study. Animals were pre-treated orally with either a human relevant dose of roflumilast (7 ?g/kg bw), a recently approved phosphodiesterase-4-inhibitor for the treatment of COPD, or dexamethasone (2 mg/kg bw) on five consecutive days. Sham-treated animals served as positive control. On day 5 a WBA was performed 6 h after the last treatment and before unilateral bronchial LPS provocation. Under general anesthesia a dose of 500 ng LPS was instilled into the left bronchus of each animal, followed by BAL of the LPS challenged left lung 18 h post provocation. A final examination including BAL was performed to test for possible long-term effects after a minimum of three weeks post LPS provocation. BAL fluid was processed and analyzed for cellular and cytokine/chemokine level. The amount
of TNF- was measured in BAL fluid and WBA supernatants using ELISA. As expected, LPS induced a remarkable and significant influx of total cells into the airways (p<0.001) with neutrophils showing the most pronounced quantitative increase. Compared with sham, pre-treatment with roflumilast resulted in a statistically significant decrease of relative and absolute neutrophil numbers in BAL of relative and absolute cell numbers (both: p=0.047). Pre-treatment with dexamethasone showed a significant reduction in relative cell numbers (p=0.047), but not in absolute neutrophil numbers (p=0.076). TNF- levels were significantly increased after LPS provocation and significantly suppressed in roflumilast (p=0.048) and dexamethasone () pre-treated animals. In WBA only pre-treatment with dexamethasone resulted in a reduced TNF- release after ex vivo LPS provocation. This further supports the important role of translational in vivo models for efficacy testing of new drugs. The significant anti-inflammatory effect of roflumilast in a human relevant dose in vivo underlines the usefulness of the common marmoset as a translational animal model for human inflammatory airway diseases.