Metallic (Ag) nanomaterials are increasingly used in a variety of commercial applications. exposure models [1C4]. The rationale for this size-dependency varied depending on the study, and included increased reactive oxygen species (ROS)  and high relative surface area leading to increased Ag dissolution [1,4] associated with relatively smaller Ag nanomaterials. Metallic is usually well established as an antimicrobial agent as Ag ions are highly reactive, readily binding to sulfur and phosphate compounds . Metallic toxicity, however, is usually complex and generally divided into the effects of the Ag particles and Ag ions BIBR 953 that are a byproduct of Ag particle oxidation and dissolution. Ag nanoparticles can interact with proteins to form stable metallic/protein complexes, whereas Ag ions are generally not free and tend to form AgCl, Ag2S, or react with organic SH-groups . The acidic pH of the biological environment can accelerate Ag dissolution such as in gastric BIBR 953 acid  or lysosomal compartments . In addition to the compounds stated above, Ag is usually known to react with reduced selenium species in biological models . Silver nanomaterial exposure has been linked to amyloidosis in some animal exposure models , although the connection with human neurodegenerative disease has not been established. Internalization of Ag into the cell is usually also divided into particle verses ionic form. Metallic ions are reported to enter cells by copper (Cu) transporter proteins (Ctr1) , and possibly by the divalent metal transporter (DMT1) . In contrast, Ag nanomaterials are internalized into cells by endocytosis , macropinocytosis , and/or passive diffusion . Endocytosis is usually the most common mechanism for Ag nanoparticle internalization. Due to the overall unfavorable zeta potential on Ag nanoparticles, scavenger receptors have been implicated as one possible mechanism associated with endocytosis, in addition to actin- and clathrin-dependent endocytosis . Uptake of solid Ag nanoparticles typically results in the release of reactive Ag ions once the particles encounter BIBR 953 the acidic pH in the lysosomal compartment of phagocytic cells. This apparently occurs more rapidly depending on the size of the Ag nanoparticles, with smaller particles dissolving faster inside the cell than larger particles, most likely due to increased surface area of the smaller particles . This presents a unique toxicological problem as Ag nanoparticles are internalized as a solid that dissolves inside the cell potentially causing disruption of the phagolysosomal membrane resulting in inflammation and toxicity [2,13]. The cellular mechanism most associated with ENM-induced inflammation is usually activation of the NLRP3 inflammasome following phagolysosome rupture or bargain . Rigid fibre-shaped ENM are most related to NLRP3 inflammasome activation [15C17], but some spherical or irregular shaped particles such as silica have also been implicated in this process . There has been a report that BIBR 953 Ag nanoparticles induced NLRP3 inflammasome activity in human monocytes . Taken together, the NLRP3 inflammasome is usually an ideal marker for ENM bioactivity in cells, such as macrophages, that are capable of forming this organic. This study used a set of four Ag nanoparticles/nanospheres (two Rabbit Polyclonal to OR4D1 sizes (20 and 110 nm) BIBR 953 and two coatings (citrate and PVP)) to test the consistency of toxicity and particle uptake results obtained from various cell models, including two murine primary alveolar macrophages (C57Bl/6, and MARCO?/?), a transformed human monocyte-like cell line (THP-1), in addition to three murine lung epithelial cell lines (LA4,.