Uptake of particles by the gastrointestinal tract occurs via membranous

epithelial cells (M-cells) on the intestinal mucosa or by persorption in epithelial cells ( Borm et al., 2006b). Silica containing phagosomes may fuse with endosomes during, or shortly after, internalisation. By this mechanism silica particles may cause damage to internal membranes allowing the leakage of endo-lysosomal selleck chemicals material into the cytoplasm leading to cytokine release. Particles may also overload the endo-lysosomal system, which could lead to an impairment of lysosomal capacity and interfere with programmed autophagic cell death and breakdown of ingested pathogens. Evidence for an active uptake mechanism of silica particles by actin- and clathrin-mediated endocytosis was found by Chung et al. (2007) and Costantini et al. (2011). Costantini et al. (2011) showed that scavenger receptors on cell surfaces are involved in silica binding and internalisation and that cell contact of silica particles with macrophages was necessary for toxicity. If uptake of silica was driven through the FccRIIA receptor-mediated

endocytosis pathway the toxicity of silica in macrophages was drastically reduced. In alveolar type II epithelial cells, heparan selleck chemical sulphate proteoglycans, especially syndeca-1, seem to play a critical role in the attachment and internalisation of positively charged SAS particles ( Orr et al., 2009). Syndecan-1 was found to mediate the initial interactions of particles at the cell surface, their coupling with actin filaments across the cell membrane,

and their subsequent internalisation. Particle size might be a limiting factor, raising the possibility that positively charged particles smaller than 100 nm might enter the cell via another mechanism. In response to a physical or chemical stressor, cells may produce reactive oxygen species (ROS). Cell injury only results if the amount of ROS produced overloads the normal anti-oxidant capacity of the cell. An increase in cellular ROS production first triggers anti-oxidant defence by the induction of phase II antioxidant enzymes via the activation of the antioxidant response element by NF-E2-related factor (Nrf)-2, a key antioxidant transcription factor found, for example, 5-FU datasheet in human lung epithelial cells. At a higher stress level, activation of MAP kinases and NF-κB cascades induces pro-inflammatory cytokine and chemokine production and release. Perturbation of the mitochondrial functions and disruption of electron transfer may result in cellular necrosis or apoptosis. Response pathways to levels of oxidative stress are shown in the following scheme (see Fig. 4, reproduced from Nel et al., 2006 with permission). After SAS exposure, ROS generation and lipid peroxidation were found in human A549 cells (Lin et al., 2006) and in conjunction with decreased intracellular GSH levels (an indicator that the cellular anti-oxidant system is overloaded) in the RAW 264.