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Cerium oxide, a diesel fuel catalyst, induces pulmonary fibrosis.
Ma JY; Mercer RR; Rao M; Barger M; Meighan T; Ma JK
Toxicologist 2010 Mar; 114(1):55-56
Cerium oxide (CeO2) has been used as a diesel fuel catalyst in Europe to lower the mass of diesel exhaust particles (DEP). The potential pulmonary toxicity of CeO2 nanoparticles, with or without DEP, has not been well characterized. Our previous studies have shown that CeO2 induced pulmonary inflammation, cytotoxicity and air/capillary injury. The objective of this study was to determine the effects of CeO2 on the induction of lung fibrosis. Male Sprague Dawley rats were exposed to CeO2 (0.5 to 7 mg/kg) by a single intratracheal instillation. Alveolar cells were isolated via bronchoalveolar lavage (BAL) at 1, 10 and 28 days post-exposure. Exposure of rats to CeO2 increased reactive oxygen species generation and apoptosis of alveolar macrophages (AM). Analysis of mRNA levels of several genes using real time RTPCR showed that CeO2 markedly increased suppressor of cytokine signaling-1 in BAL cells obtained at 1 day, which returned to the basal level at 28 days after exposure. In contrast, osteopontin (OPN) mRNA was significantly elevated in lung tissues in time-dependent manner. Exposure of rats to CeO2 or DEP alone induced arginase-1 at 28 days post-exposure, suggesting switching of AM from an inflammatory, M1, to fibrotic, M2, subset that may lead to fibrosis. Increased amounts of phospholipids were demonstrated in the BAL fluid at 10 days post exposure in CeO2-exposed lungs. Transmission electron microscopy further showed a significant amount of lamellar bodies in CeO2- and CeO2 plus DEP-exposed AM. At 28 days post-exposure, increased lung hydroxyproline content was evident in the CeO2-exposed lung tissues. Histopathological analysis of CeO2-exposed lungs showed large (alveolar sized) clumps of acellular material, but no granulomatous lesions at 28 days post-exposure. However, morphometric evidence, using sirius red staining for collagen, demonstrated that rats exposed to the combination of CeO2 plus DEP exhibited significantly greater fibrosis than CeO2 or DEP alone. These results show that CeO2 exposure induces M2 AM differentiation, apoptosis, OPN expression, and lung fibrosis.
Biological-effects; Cell-biology; Cell-damage; Cell-morphology Cellular-reactions; Chemical-hypersensitivity; Cytotoxic-effects; Diesel-emissions; Diesel-exhausts; Exposure-assessment; Exposure-levels; Exposure-methods; Inhalation-studies; Laboratory-animals; Laboratory-testing; Lung-disorders; Lung-irritants; Lymphatic-system; Particle-aerodynamics; Particulates; Pulmonary-disorders; Pulmonary-system; Pulmonary-system-disorders; Respiratory-hypersensitivity; Respiratory-irritants; Respiratory-system-disorders; Cerium-compounds
Issue of Publication
Transportation, Warehousing and Utilities
The Toxicologist. Society of Toxicology 49th Annual Meeting and ToxExpo, March 7-11, 2010, Salt Lake City, Utah