Lung function assessment in the common marmoset (Callithrix jacchus) for the evaluation of translational nonhuman primate models of lung inflammation

Introduction: Similar to the established rodents models, new translational nonhuman primate models in marmoset monkeys (Callitrix jacchus) require data about lung function. In order to gain physiological and pathological baseline data, we tested our hypotheses, that A) animals develop airway hyperresponsiveness (AHR) after pulmonary LPS-challenge and B) house-dust-mite (HDM) allergen sensitized individuals show AHR after allergen challenge. Methods: A custom-made lung-function device was specifically built for marmoset monkeys. It allows inhalation of any defined aerosol dose by simultaneous measurement of lung function in anaesthetized, orotracheally intubated and spontaneously breathing animals. Values of RL (lung resistance), Cdyn (dynamic compliance), EF50 (mid-expiratory flow) and further pulmonary variables were recoded before and after LPS administration or subsequent to HDM allergen-treatment. LPS (400 ng) or HDM (5 µg) respectively, were administered intratracheally one day prior lung function measurement. Both baseline pulmonary data and changes during provocation with increasing doses of methacholine (MCh) were measured. Results: For naïve animals inhalation of 1 µg MCh resulted in a significantly increased RL (0.63 ± 0.11 vs. 0.28 ± 0.03 cm H2O s/ml) while Cdyn and EF50 decreased (0.26 ± 0.04 vs. 0.40 ± 0.05 ml/cm H2O and 1.97 ± 0.42 vs. 3.64 ± 0.26 ml/s) compared to baseline (mean ± SEM, n = 10, p ?0.003). Provocative doses (PD) of MCh changing pulmonary variables for given percentages from baseline were calculated from individual dose response curves. After LPS-challenge of naïve animals PD100 and PD150 RL values were significantly decreased (PD100: n = 10, P = 0.050; PD150: n = 9, P = 0.023). For marmosets that were sensitized against HDM beforehand an AHR in response to MCh was also observed. PD150 RL was significantly decreased in these animals compared to naïve animals (0.62 µg vs. 1.12 µg, n = 5/10, median, p = 0.019). Discussion: Physiological and pathological lung function parameters were comprehensively examined for the first time in marmosets. Results indicate that, as expected, LPS as well as allergen-induced inflammation in allergic marmoset monkeys induces AHR. This is congruent to what is known from human subjects and characterizes the marmoset as a promising translational model for anti-inflammatory drug testing.