title: Harmful at non-cytotoxic concentrations: SiO2-SPIONs affect surfactant metabolism and lamellar body biogenesis in A549 human alveolar epithelial cells.
abstract: The pulmonary delivery of nanoparticles (NPs) is a promising approach in nanomedicine. For the efficient and safe use of inhalable NPs, understanding of NP interference with lung surfactant metabolism is needed. Lung surfactant is predominantly a phospholipid substance, synthesized in alveolar type II cells (ATII), where it is packed in special organelles, lamellar bodies (LBs). In vitro and in vivo studies have reported NPs impact on surfactant homeostasis, but this phenomenon has not yet been sufficiently examined. We showed that in ATII-like A549 human lung cancer cells, silica-coated superparamagnetic iron oxide NPs (SiO2-SPIONs), which have a high potential in medicine, caused an increased cellular amount of acid organelles and phospholipids. In SiO2-SPION treated cells, we observed elevated cellular quantity of multivesicular bodies (MVBs), organelles involved in LB biogenesis. In spite of the results indicating increased surfactant production, the cellular quantity of LBs was surprisingly diminished and the majority of the remaining LBs were filled with SiO2-SPIONs. Additionally, LBs were detected inside abundant autophagic vacuoles (AVs) and obviously destined for degradation. We also observed time- and dose-dependent changes in mRNA expression for proteins involved in lipid metabolism. Our results demonstrate that non-cytotoxic concentrations of SiO2-SPIONs interfere with surfactant metabolism and LB biogenesis, leading to disturbed ability to reduce hypophase surface tension. To ensure the safe use of NPs for pulmonary delivery, we propose that potential NP interference with LB biogenesis is obligatorily taken into account.
authors.affiliation: a Department of Biology, Biotechnical Faculty , University of Ljubljana , Ljubljana , Slovenia.
authors.forename: Veno
authors.initials: V
authors.lastname: Kononenko
authors.affiliation: b Institute of Cell Biology, Faculty of Medicine , University of Ljubljana , Ljubljana , Slovenia.
authors.forename: Andreja
authors.initials: A
authors.lastname: Erman
authors.affiliation: c Department of Molecular and Biomedical Sciences , Jožef Stefan Institute , Ljubljana , Slovenia.
authors.forename: Toni
authors.initials: T
authors.lastname: Petan
authors.affiliation: c Department of Molecular and Biomedical Sciences , Jožef Stefan Institute , Ljubljana , Slovenia.|d Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology , University of Ljubljana , Ljubljana , Slovenia.
authors.forename: Igor
authors.initials: I
authors.lastname: Križaj
authors.affiliation: e Department for Materials Synthesis , Jožef Stefan Institute , Ljubljana , Slovenia.
authors.forename: Slavko
authors.initials: S
authors.lastname: Kralj
authors.affiliation: e Department for Materials Synthesis , Jožef Stefan Institute , Ljubljana , Slovenia.
authors.forename: Darko
authors.initials: D
authors.lastname: Makovec
authors.affiliation: a Department of Biology, Biotechnical Faculty , University of Ljubljana , Ljubljana , Slovenia.
authors.forename: Damjana
authors.initials: D
authors.lastname: Drobne
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D006801:Humans; D058185:Magnetite Nanoparticles / Q000633:toxicity*; D015388:Organelles / Q000502:physiology*; D011663:Pulmonary Surfactants / Q000378:metabolism*; D012822:Silicon Dioxide / Q000633:toxicity*
chemical_list: D058185:Magnetite Nanoparticles; D011663:Pulmonary Surfactants; D012822:Silicon Dioxide
keywords: Alveolar type II cells; autophagy; lipid metabolism; magnetic nanoparticles; silica coating