Induction of pulmonary fibrosis by cerium oxide nanoparticles.
Ma-JY; Mercer-RR; Barger-M; Schwegler-Berry-D; Scabilloni-J; Ma-JK; Castranova-V
Toxicol Appl Pharmacol 2012 Aug; 262(3):255-264
Cerium compounds have been used as a diesel engine catalyst to lower the mass of diesel exhaust particles, but are emitted as cerium oxide (CeO(2)) nanoparticles in the diesel exhaust. In a previous study, we have demonstrated a wide range of CeO(2)-induced lung responses including sustained pulmonary inflammation and cellular signaling that could lead to pulmonary fibrosis. In this study, we investigated the fibrogenic responses induced by CeO(2) in a rat model at various time points up to 84 days post-exposure. Male Sprague Dawley rats were exposed to CeO(2) by a single intratracheal instillation. Alveolar macrophages (AM) were isolated by bronchial alveolar lavage (BAL). AM-mediated cellular responses, osteopontin (OPN) and transform growth factor (TGF)-beta1 in the fibrotic process were investigated. The results showed that CeO(2) exposure significantly increased fibrotic cytokine TGF-beta1 and OPN production by AM above controls. The collagen degradation enzymes, metrix metalloproteinase (MMP)-2 and -9 and the tissue inhibitor of MMP were markedly increased in the BAL fluid at 1day- and subsequently declined at 28 days after exposure, but remained much higher than the controls. CeO(2) induced elevated phospholipids in BAL fluid and increased hydrooxyproline content in lung tissue in a dose- and time-dependent manner. Immunohistochemical analysis showed MMP-2, MMP-9 and MMP-10 expressions in fibrotic regions. Morphological analysis noted collagen fibers in the lungs exposed to a single dose of 3.5mg/kg CeO(2) and sacrificed at 28 days post-exposure. Collectively, our studies show that CeO(2) induced fibrotic lung injury in rats, suggesting it may cause potential health effects.
Nanotechnology; Cerium-compounds; Diesel-emissions; Diesel-exhausts; Respiratory-system-disorders; Pulmonary-system-disorders; Lung-disorders; Immune-reaction; Lung-fibrosis; Laboratory-animals; Laboratory-testing; Fibrogenicity; Fibrosis; Exposure-assessment; Alveolar-cells; Lung-tissue; Cellular-reactions; Cytochemistry; Metalloproteins; Phospholipids; Dose-response; Histochemical-analysis; Biological-effects;
Author Keywords: Cerium oxide; Nanoparticle; Pulmonary fibrosis; Metalloproteinases; Phospholipidosis
Jane Y. Ma, PPRB/HELD, NIOSH, 1095 Willowdale Road, Morgantown, WV 26505-2888, USA
Transportation, Warehousing and Utilities
Toxicology and Applied Pharmacology