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.

Titanium dioxide nanoparticles enhance production of superoxide anion and alter the antioxidant system in human osteoblast cells

“…We have shown an elevation of ROS levels in human gingival fibroblast cells exposed to silver NPs and human lung submucosal cells exposed to silicon dioxide NPs. 17,39 Moreover, it has been reported that nanoscale TiO 2 could be phagocytized by neurons and microglia, which then release ROS: OH and O 2…”

Internalization and fate of silica nanoparticles in C2C12 skeletal muscle cells: evidence of a beneficial effect on myoblast fusion

“…[5][6][7] The presence of nanoparticles induces oxidative stress and inflammation and affects degradation pathways with an appearance of autophagosomes and lysosomal dysfunctions, leading to autophagy and apoptosis. [8][9][10] At biocompatible doses, their ability to easily enter the cell has been proposed as an asset for drug delivery, [11][12][13] cell tracking, and cell therapy, 14,15 with a particular focus on the delivery of anticancer therapeutics.…”

Size and Cell Type Dependent Uptake of Silica Nanoparticles

“…These adverse effects could be mediated by oxidative stress or/and the activation of stress-related signalling pathways [21,22]. The toxicity appears to be dependent on NP size and surface [17,[23][24][25][26]. For instance, Li et al have demonstrated that SiO 2 NP with diameters of 19, 43, 68 and 498 nm cause cytotoxicity, increased reactive oxygen species (ROS) level, DNA damage and cell cycle arrest in HepG2 cells in a size-dependent manner [23].…”