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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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)