The fate of inhaled particles in the lung - a model

PETER GEHR, BARBARA ROTHEN-RUTISHAUSER, MARTIN CLIFT, FABIAN BLANK, CHRISTINE BRANDENBERGER, ANDREA LEHMANN, LORETTA MÜLLER, MICHAEL GASSER, DAVID RAEMY

University of Bern, Bern, Switzerland

     Abstract Number: 456
     Last modified: January 6, 2010

Abstract
A number of epidemiologic studies give evidence that inhalation of fine particles and nanoparticles cause increased cardio-pulmonary morbidity and mortality. A series of structural and functional barriers protect the respiratory system against harmful and innocuous particulate material: Surfactant and aqueous liquid layer, epithelial cell layer with macrophages on top, dendritic cells at the base, basement lamina. It is still not clear how highly immunocompetent dendritic cells located at the base of the airway and alveolar epithelium but pushing slender cytoplasmic processes between the epithelial cells to the surface of the epithelial layer and eventually into the luminal space, take up inhaled and deposited antigens and how airway and alveolar macrophages on top of the epithelium may interact with each other, with the dendritic cells and with the epithelium.

Particles deposited on the surface of the airway and alveolar wall, i.e. on the surfactant film at the internal pulmonary air-liquid interface, are wetted and displaced toward the epithelium by surface forces which are exerted on them by the surfactant. This is the first step of particle translocation into the pulmonary tissue and eventually further on into other organs. Fine particles may be phagocytized by macrophages and dendritic cells. Whereas macrophages would clear these particles through mucociliary action, leaving the lungs via the airway system, dendritic cells would rather carry them to the specific immunological defence system, i.e. to lymph nodes in or closely associated with the lungs.

Nanoparticles, however, may penetrate into the pulmonary tissue and they may be taken up by or enter cells by alternative mechanisms, i.e. by endocytosis, through pores or passively by adhesive interaction with cell membranes. Passive uptake may occur by electrostatic forces, including hydrogen bond, van der Waals and hydrophobic interactions. It is assumed that it is by these mechanisms that nanoparticles can penetrate through the air-blood tissue barrier into the capillaries on their way of translocation through the pulmonary tissue, leaving the lungs via the vascular system. They will be transported by the blood stream to other organs like the liver, the spleen, the kidneys, the heart and the brain where they may enter the tissue by yet unknown mechanisms and be deposited.

With a triple cell co-culture model of the human epithelial airway wall, we could demonstrate that dendritic cells extend cytoplasmic processes between the epithelial cells through the tight junctions into the luminal space to collect particles deposited on the internal pulmonary surface and to transport them across the epithelium through these cytoplasmic processes. Macrophages, similar to dendritic cells, may push slender cytoplasmic processes through the tight junctions and between the epithelial cells to the base of the epithelial layer.

Dendritic cells may also interact with particle loaded airway macrophages on top of the epithelium. Based on these findings, we postulate that these two cell types, acting as sentinels in the airways and alveoli, build a trans-epithelial interacting cellular network, which makes them an efficient intraepithelial complex cellular defence system against inhaled particulate antigens.