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Engineered nanoparticles (ENM) cause lung pathology by increasing lysosomal membrane permeability and activation of the NLRP3 inflammasome in macrophages.
Holian A; Hamilton R; Girtsman T; Migliaccio C; Buford M; Shaw P; Herritt L; Mitra S; Sager T; Porter D; Wu N
Eur J Clin Invest 2013 Apr; 43(Suppl 1):5
Background: The purpose of the study was to determine the mechanism of bioactivity of ENM by linking their ability to cause lysosomal dysfunction and activation of the NLRP3 inflammasome in macrophages to lung pathology. Materials and methods: A library (raw and modified MWCNT, metal oxides of different shapes and modifications, and silver of different sizes) of nanomaterials were prepared, characterized and tested in vitro using THP-1 macrophages, alveolar macrophages isolated from C57Bl/6 mice and in vivo using C57Bl/6 mice. Assessments were made of: uptake, lysosomal dysfunction, cathepsin B release, NLRP3 inflammasome activation, IL-1beta release, lung inflammation and pathology. Results: All ENM were effectively taken up by macrophages. However, only bioactive ENM caused phagolysosomal membrane disruption, cathepsin B release, NLRP3 inflammasome activation and IL-1beta release from both macrophage models. THP-1 cells proved to be a more sensitive model than primary macrophages. Furthermore, the relative activity of ENM in THP-1 cells was a good predictor of in vivo NLRP3 inflammasome activation, inflammation and lung pathology. Long aspect ENM of the same material were more active than spherical and dependent on length. Carboxylation of ENM decreased bioactivity and surface area was a good predictor of bioactivity of spherical materials. Conclusions: ENM cause lung inflammation and injury through activation of the NLRP3 inflammasome and there is now increasing knowledge linking ENM structure with bioactivity.
Nanotechnology; Respiratory-system-disorders; Pulmonary-system-disorders; Lung-cells; Lung-disorders; Lung-function; Lung-irritants; Lung-tissue; Pathology; Immune-reaction; Bioactivation; Silver-compounds; Metal-oxides; In-vitro-study; Alveolar-cells; In-vivo-study; Laboratory-animals; Laboratory-testing; Cellular-uptake; Phagocytic-activity; Analytical-models; Cellular-reactions
European Journal of Clinical Investigation
NJ; MT; OH; WV
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