Investigating the impact of polarization on foamy macrophage induction by amiodarone in vitro.

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Investigating the impact of polarization on foamy macrophage induction by amiodarone in vitro

E Hoffman, A Martin, DYS Chau, D Murnane, V Hutter

Department of Pharmacy, Pharmacology and Postgraduate Medicine, School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, AL10 9AB.

Summary

Many new inhaled medicines fail during development due to the induction of a “foamy” alveolar macrophage response in pre-clinical studies. There is limited understanding if a highly vacuolated macrophage phenotype 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. It is currently unknown if foamy macrophage responses are triggered by macrophage polarization. The aim of this study was to investigate macrophage polarization and cellular responses of alveolar-like macrophages derived from the human monocyte cell line U937, to different stimuli. Amiodarone and etoposide were selected as foamy macrophage inducers and apoptotic agents, to investigate the link between macrophage response and M1/M2 activation. U937 cells were differentiated to an alveolar-like macrophage phenotype and expressed surface M0 marker, CD11b. Differentiated cells were then activated to M1 or M2 cells and assessed for their expression of the M1 marker, CXCL10 or M2 marker CD206, which was observed to be 10% and 12% respectively. A significant elevation (p<0.05) of phospholipid accumulation within the cells exposed to 10 µM amiodarone was observed, which was greater for M2- than M1-activated macrophages. This change was accompanied by lower expression of CXCL10, suggesting that amiodarone may reverse M1-activation. Improved understanding of macrophage subtype responses to inhaled stimuli is necessary for further progress in this area, and to fully characterise the foamy macrophage response to elucidate its role in airway pathophysiology.