Airway hyper-responsiveness in lipopolysaccharide-challenged common marmosets (Callithrix jacchus)

Animal models with a high predictive value for human trials are needed to develop novel human-specific therapeutics for respiratory diseases. The aim of the present study was to examine lung-function parameters in marmoset monkeys (Callithrix jacchus) that can be used to detect pharmacologically or provocation-induced AHR (airway hyper-responsiveness). Therefore a custom-made lung-function device that allows application of defined aerosol doses during measurement was developed. It was hypothesized that LPS (lipopolysaccharide)-challenged marmosets show AHR compared with non-challenged healthy subjects. Invasive plethysmography was performed in 12 anaesthetized orotracheally intubated and spontaneously breathing marmosets. Pulmonary data of RL (lung resistance), Cdyn (dynamic compliance), EF50 (mid-expiratory flow), Poes (oesophageal pressure), MV (minute volume), respiratory frequency (f) and VT (tidal volume) were collected. Measurements were conducted under baseline conditions and under MCh (methacholine)-induced bronchoconstriction. The measurement was repeated with the same group of animals after induction of an acute lung inflammation by intratracheal application of LPS. PDs (provocative doses) of MCh to achieve a certain increase in RL were significantly lower after LPS administration. AHR was demonstrated in the LPS treated compared with the naïve animals. The recorded lung-function data provide ground for pre-clinical efficacy and safety testing of anti-inflammatory substances in the common marmoset, a new translational NHP (non-human primate) model for LPS-induced lung inflammation. CLINICAL PERSPECTIVES The established invasive lung-function testing in orotracheally intubated marmosets provides ground for pre-clinical safety and efficacy testing of pharmaceuticals in this species. Readout parameters that were previously only accessible in the classic rodent model are now established for a new NHP model. There is growing demand of marmosets as the non-rodent 'second' species in pre-clinical tests. The technique described to measure lung function in an NHP model will help to support the current need for models with a high predictive power for human clinical trials. It furthermore incorporates the 3-Rs. Marmosets are handled similar to human probands and can potentially be used for multiple studies, which reduce the animal numbers.