Matrix metalloproteinases 2 and 9 and tissue inhibitors of metalloproteinase 1 in cerium oxide induced pulmonary fibrosis.
Ma-JY; Mercer-RR; Barger-M; Ma-JK; Castranova-V
Toxicologist 2011 Mar; 120(Suppl 2):446
Cerium compounds have been used as a diesel engine catalyst to lower the mass of diesel exhaust particles, but are emitted as cerium oxide nanoparticles (CeO2) in the diesel exhaust. Our previous studies have shown that CeO2 induced pulmonary Cerium compounds have been used as a diesel engine catalyst to lower the mass of diesel exhaust particles, but are emitted as cerium oxide nanoparticles (CeO2) in the diesel exhaust. Our previous studies have shown that CeO2 induced pulmonary inflammation, air/capillary injury, M2 AM differentiation and lung fibrosis. In this study, we investigated the mechanisms involved in CeO2-induced pulmonary fibrosis. Male Sprague Dawley rats were exposed to CeO2 (0.15 to 7 mg/kg) by a single intratracheal instillation and sacrificed at 1, 10, 28 and 84 days after exposure. Alveolar macrophages (AM) were isolated by bronchial alveolar lavage (BAL) and the first BAL fluid was saved for further analysis. The activity of osteopontin (OPN), a multifunctional matricellular protein expressed during inflammation and repair, in AM cultured media was significantly increased at 10 and 28 days post exposure. Collagen degradation enzymes, matrix metalloproteinases (MMPs)-2 and - 9 and tissue inhibitor of MMP-1 (TIMP-1), in first lavage fluid were markedly induced by CeO2 at 1 day- and subsequently declined to a lower level at 28 days-post exposure but remained significantly higher than the controls. Hydroxyproline content in lung tissues, a measure for fibrosis, was significantly elevated in the CeO2- exposed lung tissues in a dose- and time-dependent manner. Morphological analysis showed enhanced collagen fibers in CeO2 (3.5 mg/kg)-exposed lungs at 28 days post-exposure. In addition, CeO2 particles were detected in lung tissue and fibroblasts isolated from CeO2 (3.5 mg/kg)-exposed rats at 28 days after exposure using CytoViva's illumination technology. These results demonstrate that exposure of rats to CeO2 induced fibrotic lung injury through induction of OPN and the imbalance of MMPs and TIMP in extracellular matrix remodeling. These findings suggest potential health effects of CeO2 exposure.
Biological-effects; Cell-biology; Cell-damage; Cellular-reactions; Cytotoxic-effects; Diesel-exhausts; Exposure-methods; Fibrogenicity; Fibrous-bodies; Immunotoxins; Laboratory-animals; Lung-disorders; Lung-fibrosis; Lung-irritants; Lung-tissue; Molecular-biology; Nanotechnology; Particle-aerodynamics; Particulates; Pulmonary-disorders; Pulmonary-system-disorders; Quantitative-analysis; Respiratory-hypersensitivity; Respiratory-irritants; Respiratory-system-disorders; Statistical-analysis; Tissue-disorders; Toxic-effects; Toxic-materials; Animal-studies; Animals
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The Toxicologist. Society of Toxicology 50th Annual Meeting and ToxExpo, March 6-10, 2011, Washington, DC