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Persistent pulmonary inflammation, airway mucous metaplasia and migration of multiwalled carbon nanotubes from the lung after subchronic exposure.

Hubbs-A; Mercer-RR; Coad-JE; Battelli-LA; Willard-PA; Sriram-K; Wolfarth-M; Castranova-V; Porter-D
Toxicologist 2009 Mar; 108(1):457
Multi-walled carbon nanotubes (MWCNTs) are manufactured carbon compounds with many commercial applications. The fiber-like dimensions of MWCNTs, their durability, and ability to cause peritoneal inflammation are reminiscent of asbestos, but their toxicity is incompletely investigated. To address the hypothesis that MWCNTs cause persistent morphologic changes and migrate beyond the lung, C57BL/6J mice were exposed by pharyngeal aspiration to 20 or 80 ug MWCNTs (mean dimensions of 4.2 um x 49 nm) or vehicle. Lung and tracheobronchial lymph node were collected for histopathology 7 and 56 days after exposure. MWCNTs principally accumulated in macrophages and caused granulomatous inflammation. Inflammation extended to the pleura in 7/8 and 4/8 MWCNT-exposed mice at 7 and 56 days, respectively. Both short and long MWCNTs projected beyond the cytoplasmic margins of some macrophages, indicating incomplete phagocytosis or cytoplasmic penetration after phagocytosis. Airway epithelial changes included hypertrophy, cellular atypia and mucous metaplasia. Sirius Red staining demonstrated fibrosis of granulomas and alveolar septa by 7 days post-exposure. Activated caspase-3 and TUNEL assays of the 80 mu g exposure group at 7 days post-exposure demonstrated increased apoptosis in alveolar macrophages. MWCNTs accumulated in the draining tracheobronchial lymph nodes and were principally intracellular. At 56 days post-exposure, subpleural lymphatics were focally dilated in one mouse and peribronchiolar lymphatics were dilated in all 4 mice in the 80 mu g exposure. Subpleural lymphatics were also dilated in one mouse at 7 days post-exposure. In 4 mice, including both mice with subpleural lympangiectasia, MWCNTs appeared to penetrate the pleura. These findings demonstrate that MWCNTs cause persistent pulmonary inflammation, can be translocated within the lung by alveolar macrophages, can migrate from the lung to the regional lymph node and can penetrate the cytoplasm of macrophages.
Biological-effects; Biological-factors; Cell-morphology; Cellular-reactions; Cell-biology; Cytology; Exposure-assessment; Exposure-levels; Exposure-methods; Fibrosis; Fibrogenicity; Inhalation-studies; Irritants; Laboratory-animals; Lung-cells; Lung-irritants; Lymph-nodes; Lymphatic-system; Microscopic-analysis; Particle-aerodynamics; Particulates; Pulmonary-function; Respiratory-irritants; Respiratory-hypersensitivity; Risk-factors; Statistical-analysis; Tissue-culture; Toxic-effects; Tissue-culture; Nanotechnology
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The Toxicologist. Society of Toxicology 48th Annual Meeting and ToxExpo, March 15-19, 2009, Baltimore, Maryland