Novel alveolar macrophage-like model (ImmuPHAGE) as a platform for better mechanistic understanding for the fate of inhaled medicines.

Alveolar macrophages are the first line of defence against inhaled particulates in the respiratory system. Nearly 40% of inhaled medicines fail in preclinical in vivo studies due to the presence of abnormal alveolar morphology and functionality. It is unclear if these alveolar macrophage responses affect health and their relevance to humans. Therefore, there are questions raised about the relevance and utility of current preclinical models. ImmuPHAGE is alveolar macrophage-like model which closely resemble the morphology and functionality of human macrophages resident in the lungs. The aim of this work was to establish a robust human alveolar macrophage model in vitro to accurately and in reproducible way evaluate the responses of alveolar macrophages and to ascertain if this could provide a more accurate prediction of inhaled safety assessment. The model was characterised in detail including viability (cell proliferation, metabolic activity, membrane integrity), functionality (phagocytosis activity) and phenotype (a panel of CD markers) for over 5 weeks. Additionally, the model was exposed to a panel of compounds of alveolar toxicity via various mechanical pathways (e.g. apoptosis, inflammation and phospholipidosis inducers). ImmuPHAGE maintained good viability and functionality in 5 weeks culture. The cells responses were highly reproducible and allowed detailed understanding of immune responses in the small airway including clearance, inflammation and pathological macrophage responses. This novel in vitro platform can provide new insights to mechanistic understandings for the fate of inhaled substances in human lungs.