Marmoset monkeys as a preclinical model in respiratory research

Increasing incidence and substantial morbidity and mortality of respiratory diseases including ALI/ARDS, COPD, and asthma bronchiale requires the development of new effective therapeutics. In this context, highly human-specific and biologically-active substances targeting cell signaling pathways or directed against cytokines and adhesion molecules display the most promising treatment strategies. For the preclinical testing of these biologically active substances, however, suitable predictive human relevant animal models are needed. The aim of the present work was to evaluate the suitability of the small anthropoid New World monkey common marmoset to serve as a preclinical animal model for respiratory diseases. Airway obstruction and inflammation represent important features of these diseases and have been analyzed in ex vivo and in vivo approaches. Using PCLS, the mechanisms of bronchoconstriction were investigated in marmoset monkeys, as well as in three Old World monkey species including, cynomolgus macaques, rhesus macaques, and olive baboons. The results were then compared to published data of humans and commonly used small laboratory animals. Furthermore, in accordance with previously published inflammation models in humans, a tiered approach of acute LPS-induced lung inflammation was designed in marmoset monkeys ex vivo and in vivo. The treatment of marmoset PCLS with various bronchoconstrictors including methacholine, histamine, serotonin, ET-1 and the Tx-prostanoid agonist U46619 displayed huge similarities compared to human mechanisms of bronchoconstriction. Additionally, exposure of marmoset PCLS to LPS, a strong activator of the innate immune system, revealed huge analogies to equally treated human PCLS regarding TNF-α release. This LPS-induced TNF-α release was significantly reduced by the PDE4 inhibitor roflumilast with the same potency as in human PCLS resulting in closely related pIC50. The pre-treatment of marmoset monkeys with the human dosage of roflumilast for 5 consecutive days revealed a significant lower influx of neutrophil granulocytes, as well as TNF-α in BAL fluid 18 hours after LPS challenge. Furthermore, as in human PCLS the corticosteroid dexamethasone also revealed strong immunosuppressive effects in LPS-induced lung inflammation in marmoset monkeys. Along with these findings, we were able to show that PCLS of marmoset monkeys are a suitable model for investigating mechanisms of bronchoconstriction in the context of obstructive lung diseases. Furthermore, the tiered approach of LPS-induced inflammation in marmoset monkeys represents a new preclinical model for evaluating therapeutic efficacy of new-class pharmaceuticals targeting inflammatory features of respiratory diseases.