Biokinetic Modeling of Nanoparticle Interactions with Lung Alveolar Epithelial Cells

Abstract

Many studies on the health effects of inhaled ambient and engineered nanomaterials (ENMs) have provided information on nanoparticle toxicity and translocation across airway and alveolar epithelial barriers. Various inhaled ENMs (e.g., gold and iridium nanoparticles) have been reported to partially cross the air-blood barrier in the lung, enter the circulation and distribute into several end organs, including heart, liver, spleen and kidney. Using an in vitro primary rat alveolar epithelial cell (AEC) monolayer model, we reported transport rates of relatively nontoxic polystyrene nanoparticles (PNPs), which appear to be taken up via nonendocytic processes into AECs. PNPs internalized into cytoplasm then trigger autophagy, followed by delivery of PNPs from autophagosomes into lysosomes, from where PNPs can be exocytosed. We used the data from these in vitro experiments to perform biokinetic modeling that incorporates the processes associated with internalization and intracellular distribution of PNPs, autophagy, lysosomal exocytosis of PNPs, and several putative mechanisms of action that extend our previous understanding of AEC processing of PNPs. Results indicate that entry of PNPs into AECs, subsequent activation of autophagy by cytosolic PNPs, accumulation of PNPs in lysosomes, and lysosomal exocytosis are interwoven by complex proposed regulatory mechanisms. These findings are consistent with the presence of intracellular interactions that provide potential new insights into how inhaled nanoparticles may be mechanistically linked to the development of acute and chronic lung injury.