TY - BOOK ID - 127171817 TI - Contribution of interstitial and alveolar macrophages to ITO-induced PAP AU - De Gussem, Valentin AU - Huaux, François AU - UCL.. FASB - Faculté de pharmacie et des sciences biomédicales PY - 2015 PB - Bruxelles: UCL. Faculté de pharmacie et des sciences biomédicales, DB - UniCat KW - Lung Diseases, Interstitial KW - Macrophages KW - Pulmonary Wedge Pressure UR - https://www.unicat.be/uniCat?func=search&query=sysid:127171817 AB - Lung macrophages are essential for alveolar homeostasis and foreign body removal. Macrophage dysfunction can result in a pathological accumulation of surfactants, lipids and proteins in the alveoli called pulmonary alveolar proteinosis (PAP). Inhalation of indium-containing particles (ICPs) such as indium-tin oxide (ITO) is specifically associated with macrophage toxicity and PAP development. In vitro studies have demonstrated that ITO particles are phagocytosed and dissolved by macrophages which subsequently release ionic indium, the primary cytotoxic compound for these cells. Here, we performed in vivo and ex vivo studies to determine how ITP particles affect alveolar (AM) and interstitial (IM) macrophages, the two main macrophage populations of the lungs. After ITO instillation in mice, we observed a depletion of the AM subpopulation that coincided with PAP formation. In contrast, IM were persistently accumulated in treated mice, suggesting that AM is the main target of ITO toxicity. Paradoxically, IM phagocytosed more ITO particles and were more sensitive to ITO exposure than AM ex vivo. In contrast, ionic indium was highly cytotoxic for AM in comparison to IM. Our data obtained by using AM and IM co-cultures and endocytosis inhibitors suggested that IM phagocytose ITO particles and release ionic indium that forms complexes particularly cytotoxic for AM. These results suggested that both IM and AM contribute to ITO-induced PAP in mice. In addition, the specific depletion of AM in ITO-treated mice was related to a defect of IL-1α (not GM-CSF), an essential autocrine cytokine for AM replenishment during lung responses to particles. We concluded that alveolar clearance defect and PAP development after ICPs exposure result from the release of ionic indium and the abrogation of AM self-maintenance. ER -