Evaluating the response of alveolar macrophages to inhaled medicines (360G-Wellcome-207202_Z_17_Z)

Many new inhaled medicines fail during development due to the induction of a "foamy" alveolar macrophage response in pre-clinical studies. It is not fully understood if a highly vacuolated macrophage response to an inhaled stimulus is adverse or adaptive. Macrophages dynamically alter their phenotype and function depending on their underlying microenvironment resulting in abnormal shifts in their polarization state between classically (M1) and alternatively (M2) activated. M1 describes the classically activated macrophage which acts as an innate immune effector cell characterised by increased production of pro-inflammatory cytokines. M2 macrophages are alternatively activated, responsible for signalling wound-healing cell secreting anti-inflammatory cytokines. At the university, high-content screens have been developed to assess macrophage cell health and morphometric changes induced by different stimuli. However, the mechanism of these changes has not been explained and it is unknown if macrophage responses are triggered by macrophage polarization. The aim of this study is to investigate macrophage polarization and cellular responses of alveolar-like macrophages derived from the human monocyte cell line U937, to different chemical inducers. Improved understanding of macrophage responses to inhaled stimuli is necessary for further progress in this area, and to fully characterise the macrophage response to elucidate its role in airway pathophysiology.