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Effects of combined exposure to diesel exhaust particles and cerium oxide nanoparticles on the response to endotoxin in rats.

Dolash-BD; Barger-MW; Castranova-V; Ma-JY
Toxicologist 2012 Mar; 126(Suppl 1):69
Cerium compounds have been used as diesel fuel catalysts to lower the burn-off temperature of diesel exhaust particles (DEP). This catalysis increases the lifetime and efficiency of exhaust filters and lowers DEP emissions; however results in cerium oxide nanoparticles (CNP) released in the exhaust. Previous studies from our laboratory have shown that DEP and/or CNP induced lung inflammation, damage and fibrosis. This study focuses on the effects of DEP- and/or CNP-exposed rats on the susceptibility to endotoxin. Male Sprague-Dawley rats were treated by intratracheal (IT) instillation of DEP (5 mg/kg body weight) and/or CNP (1 mg/kg body weight). After 3 days, the rats were exposed to lipopolysaccharide (LPS) by IT instillation (1 mg/kg body weight) and then sacrificed after 3 additional days. CNP, DEP and CNP+DEP exposures induced neutrophilia, enlarged macrophages, and released inflammatory mediators, interleukin-12 (IL-12) and osteopontin (OPN), into the bronchial alveolar lavage (BAL) fluid. The exposure to LPS further increased neutrophilia, but did not affect particle-induced cytotoxicity and air/capillary damage. LPS exposure did not affect IL-12 and OPN production in rats treated with DEP or CNP+DEP, but significantly increased IL-12 and OPN in BAL fluid of CNP-treated rats. Increased transforming growth factor beta (TGF-beta), an important mediator of fibrosis detected in alveolar macrophages isolated from all particle-exposed rats. TGF-beta induction was further enhanced in response to LPS. A significant increase in matrix metalloproteinase-9 (MMP-9) was seen in BAL from CNP- and CNP+DEP-exposed rats. Tissue inhibitor of metalloproteinase 1 (TIMP-1), a MMP-9 inhibitor, was markedly increased in particle-exposed groups. LPS exposure did not significantly alter particles-induced MMP-9, but markedly enhanced TIMP-1 levels. These results suggest endotoxin exposure significantly increased TGF-beta production, but lowered the MMP-9/TIMP-1 ratio. These changes may lead to extracellular matrix damage and fibrotic development, leading to health concerns.
Nanotechnology; Laboratory-animals; Laboratory-techniques; Laboratory-testing; Exposure-assessment; Exposure-methods; Exposure-levels; Heart; Lung; Pulmonary-system; Immune-reaction; Dose-response; Vasoactive-agents; Particulates; Diesel-exhausts; Cerium-compounds
7440-45-1; 1306-38-3
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NIOSH Division
Priority Area
Transportation, Warehousing and Utilities
Source Name
The Toxicologist. Society of Toxicology 51st Annual Meeting and ToxExpo, March 11-15, 2012, San Francisco, California