| Ultrafine Particles Cross Cellular Membranes by Nonphagocytic Mechanisms in Lungs and in Cultured Cells Marianne Geiser,1 Barbara Rothen-Rutishauser,1 Nadine
Kapp,1 Samuel Schürch,1,2 Wolfgang Kreyling,3 Holger
Schulz,3 Manuela Semmler,3 Vinzenz Im Hof,4 Joachim
Heyder,3 and Peter Gehr1 1Institute for Anatomy, University of Bern, Bern, Switzerland; 2Department
of Physiology and Biophysics, Faculty of Medicine, The University of Calgary,
Calgary, Alberta, Canada; 3GSF-National Research Center for Environment
and Health, Institute for Inhalation Biology, Neuherberg/Munich, Germany; 4Institute
of Pathophysiology, University of Bern, Bern, Switzerland Abstract
High concentrations of airborne particles have been associated with increased pulmonary and cardiovascular mortality, with indications of a specific toxicologic role for ultrafine particles (UFPs ; particles < 0.1 µm) . Within hours after the respiratory system is exposed to UFPs, the UFPs may appear in many compartments of the body, including the liver, heart, and nervous system. To date, the mechanisms by which UFPs penetrate boundary membranes and the distribution of UFPs within tissue compartments of their primary and secondary target organs are largely unknown. We combined different experimental approaches to study the distribution of UFPs in lungs and their uptake by cells. In the in vivo experiments, rats inhaled an ultrafine titanium dioxide aerosol of 22 nm count median diameter. The intrapulmonary distribution of particles was analyzed 1 hr or 24 hr after the end of exposure, using energy-filtering transmission electron microscopy for elemental microanalysis of individual particles. In an in vitro study, we exposed pulmonary macrophages and red blood cells to fluorescent polystyrene microspheres (1, 0.2, and 0.078 µm) and assessed particle uptake by confocal laser scanning microscopy. Inhaled ultrafine titanium dioxide particles were found on the luminal side of airways and alveoli, in all major lung tissue compartments and cells, and within capillaries. Particle uptake in vitro into cells did not occur by any of the expected endocytic processes, but rather by diffusion or adhesive interactions. Particles within cells are not membrane bound and hence have direct access to intracellular proteins, organelles, and DNA, which may greatly enhance their toxic potential. Key words: aerosol, erythrocytes, lungs, macrophages, microscopy, nanoparticles, rats, surfactant. Environ Health Perspect 113:1555-1560 (2005) . doi:10.1289/ehp.8006 available via http://dx.doi.org/ [Online 26 May 2005]
Address correspondence to M. Geiser, Institute of Anatomy, University of Bern, Baltzerstrasse 2, CH-3000 Bern 9, Switzerland. Telephone: 41-31-631-8475. Fax: 41-31-631-3807. E-mail: geiser@ana.unibe.ch We thank S. Frank, B. Haenni, B. Kupferschmid, and B. Tschirren for excellent technical assistance and L.M. Cruz-Orive for his help with the lung sampling design. This study was supported by the Swiss National Science Foundation ; the Swiss Agency for the Environment, Forest, and Landscape ; and the Silva Casa Foundation. The authors declare they have no competing financial interests. Received 9 February 2005 ; accepted 26 May 2005. The full version of this article is available for free in HTML or PDF formats. |
