Internal contamination by inhalation of plutonium poorly soluble compounds leads to their long time retention in alveolar macrophages inducing delayed pathology development. As previous studies highlighted co-localization of retained Pu and inflammatory lesions, this study was designed to assess the combined effect of the reference treatment (DTPA) and anti-inflammatory drugs on Pu-induced early response of macrophages in vitro. Pu colloids, mimicking poorly soluble Pu, were characterized using filtration and solid-state nuclear track detectors CR39. Their bioavailability was determined using a biphasic acellular model. Treatment effects on Pu dissolution and release as well as on Pu-induced pro-inflammatory response were assessed over 7 days on macrophage-like cells. DTPA treatment, associated or not with anti-inflammatory drug, increased Pu dissolution and release from contaminated THP-1 differentiated cells after 7 days. Significant decreases in Pu-induced IL-8 and MCP-1 secretions were also observed with anti-inflammatory treatment associated or not with DTPA. This study highlighted the ability of DTPA to partially dissolve a poorly soluble form of Pu as well as the ability of anti-inflammatory drugs to modulate Pu-induced pro-inflammatory response in macrophage-like cells. These treatments seem a promising strategy to improve the clinical management of Pu pulmonary contaminations and to limit delayed pulmonary pathology occurrence.