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The Role of Macrophages in the Clearance of Inhaled Ultrafine Titanium Dioxide Particles

¹ Institute of Anatomy, University of Bern, Bern, Switzerland; and ² GSF—National Research Center for Environment and Health, Institute for Inhalation Biology, Neuherberg/Munich, Germany

Correspondence and requests for reprints should be addressed to M. Geiser, Ph.D., Institute of Anatomy, University of Bern, Baltzerstrasse 2, CH-3000 Bern 9, Switzerland. E-mail: geiser{at}ana.unibe.ch

The role of macrophages in the clearance of particles with diameters less than 100 nm (ultrafine or nanoparticles) is not well established, although these particles deposit highly efficiently in peripheral lungs, where particle phagocytosis by macrophages is the primary clearance mechanism. To investigate the uptake of nanoparticles by lung phagocytes, we analyzed the distribution of titanium dioxide particles of 20 nm count median diameter in macrophages obtained by bronchoalveolar lavage at 1 hour and 24 hours after a 1-hour aerosol inhalation. Differential cell counts revealing greater than 96% macrophages and less than 1% neutrophils and lymphocytes excluded inflammatory cell responses. Employing energy-filtering transmission electron microscopy (EFTEM) for elemental microanalysis, we examined 1,594 macrophage profiles in the 1-hour group (n = 6) and 1,609 in the 24-hour group (n = 6). We found 4 particles in 3 macrophage profiles at 1 hour and 47 particles in 27 macrophage profiles at 24 hours. Model-based data analysis revealed an uptake of 0.06 to 0.12% ultrafine titanium-dioxide particles by lung-surface macrophages within 24 hours. Mean (SD) particle diameters were 31 (8) nm at 1 hour and 34 (10) nm at 24 hours. Particles were localized adjacent (within 13–83 nm) to the membrane in vesicles with mean (SD) diameters of 592 (375) nm at 1 hour and 414 (309) nm at 24 hours, containing other material like surfactant. Additional screening of macrophage profiles by conventional TEM revealed no evidence for agglomerated nanoparticles. These results give evidence for a sporadic and rather unspecific uptake of TiO₂-nanoparticles by lung-surface macrophages within 24 hours after their deposition, and hence for an insufficient role of the key clearance mechanism in peripheral lungs.

Key Words: clearance • electron filtering transmission electron microscopy • lungs • macrophages • nanoparticles

CLINICAL RELEVANCE Ineffective macrophage clearance of inhaled nanoparticles from peripheral lungs prolongs their residence time in lungs and/or favors their translocation into the lung tissue and into the vasculature, potentially enhancing adverse health effects.