title: Mechanisms of toxicity of amorphous silica nanoparticles on human lung submucosal cells in vitro: protective effects of fisetin.
abstract: There is growing evidence that amorphous silica nanoparticles (SiO₂-NP) can cause an inflammatory response in the lung. We studied in vitro the effects of exposing human lung submucosal cells to SiO₂-NP of various sizes (10, 150, and 500 nm) for 2-24 h. Cell survival, reactive oxygen species (ROS), malondialdehyde (MDA) levels, cytokine production, inflammatory gene expression, and genotoxicity were measured after exposure of Calu-3 cells to 10SiO₂-NP in the presence or absence of the flavanoid fisetin and an antioxidant enzyme catalase. The exposure of Calu-3 cells to 10SiO₂-NP resulted in (1) increased cytotoxicity and cell death in a time- and concentration-dependent manner, with a lethal concentration (LC₅₀) of 9.7 μg/mL after 24 h; (2) enhanced gene expression of interleukin (IL)-6, IL-8, and matrix metalloproteinase-9; (3) a significant correlation between increases in MDA and cytotoxicity at 18 h; (4) ROS production; (5) IL-6 and IL-8 release; and (6) up-regulation of the pro-apoptotic genes, p53 and caspase-3. Cell death and inflammatory reactions were attenuated by fisetin and catalase. We observed that 150- and 500SiO₂-NP exerted no toxic effects on Calu-3 cells. In conclusion, the nanotoxicity of amorphous 10SiO₂-NP on submucosal cells is associated with inflammation, the release of ROS leading to apoptosis, and decreased cell survival. The nanotoxic effects of 10SiO₂-NP can be decreased by fisetin and catalase treatment, implicating oxidative stress in this injury.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin, Ireland. mccartj7@tcd.ie
authors.forename: Joanna
authors.initials: J
authors.lastname: McCarthy
authors.forename: Iwona
authors.initials: I
authors.lastname: Inkielewicz-Stępniak
authors.forename: J Jose
authors.initials: JJ
authors.lastname: Corbalan
authors.forename: Marek W
authors.initials: MW
authors.lastname: Radomski
mesh_terms: D053148:Caspase 3 / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003603:Cytotoxins / Q000633:toxicity*; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D053758:Nanoparticles / Q000633:toxicity*; D010316:Particle Size; D017382:Reactive Oxygen Species / Q000378:metabolism; D012822:Silicon Dioxide / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D003603:Cytotoxins; D005419:Flavonoids; D044948:Flavonols; D015850:Interleukin-6; D016209:Interleukin-8; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D012822:Silicon Dioxide; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9; C017875:fisetin