title: Induction of pulmonary fibrosis by cerium oxide nanoparticles.
abstract: 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)-β1 in the fibrotic process were investigated. The results showed that CeO(2) exposure significantly increased fibrotic cytokine TGF-β1 and OPN production by AM above controls. The collagen degradation enzymes, matrix metalloproteinase (MMP)-2 and -9 and the tissue inhibitor of MMP were markedly increased in the BAL fluid at 1 day- 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 hydroxyproline 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 increased collagen fibers in the lungs exposed to a single dose of 3.5mg/kg CeO(2) and euthanized 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.
authors.affiliation: Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA. jym1@cdc.gov
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Ma
authors.forename: Robert R
authors.initials: RR
authors.lastname: Mercer
authors.forename: Mark
authors.initials: M
authors.lastname: Barger
authors.forename: Diane
authors.initials: D
authors.lastname: Schwegler-Berry
authors.forename: James
authors.initials: J
authors.lastname: Scabilloni
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Ma
authors.forename: Vincent
authors.initials: V
authors.lastname: Castranova
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002563:Cerium / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006909:Hydroxyproline / Q000032:analysis; D008168:Lung / Q000737:chemistry / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000032:analysis; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000633:toxicity*; D053495:Osteopontin / Q000032:analysis; D011658:Pulmonary Fibrosis / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000032:analysis
chemical_list: D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D002563:Cerium; C030583:ceric oxide; D053506:Matrix Metalloproteinase 10; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D006909:Hydroxyproline