skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Interactive effects of cerium oxide and diesel exhaust nanoparticles on inducing pulmonary fibrosis

Abstract

Cerium compounds have been used as a fuel-borne catalyst to lower the generation of diesel exhaust particles (DEPs), but are emitted as cerium oxide nanoparticles (CeO{sub 2}) along with DEP in the diesel exhaust. The present study investigates the effects of the combined exposure to DEP and CeO{sub 2} on the pulmonary system in a rat model. Specific pathogen-free male Sprague–Dawley rats were exposed to CeO{sub 2} and/or DEP via a single intratracheal instillation and were sacrificed at various time points post-exposure. This investigation demonstrated that CeO{sub 2} induces a sustained inflammatory response, whereas DEP elicits a switch of the pulmonary immune response from Th1 to Th2. Both CeO{sub 2} and DEP activated AM and lymphocyte secretion of the proinflammatory cytokines IL-12 and IFN-γ, respectively. However, only DEP enhanced the anti-inflammatory cytokine IL-10 production in response to ex vivo LPS or Concanavalin A challenge that was not affected by the presence of CeO{sub 2}, suggesting that DEP suppresses host defense capability by inducing the Th2 immunity. The micrographs of lymph nodes show that the particle clumps in DEP + CeO{sub 2} were significantly larger than CeO{sub 2} or DEP, exhibiting dense clumps continuous throughout the lymph nodes. Morphometric analysis demonstratesmore » that the localization of collagen in the lung tissue after DEP + CeO{sub 2} reflects the combination of DEP-exposure plus CeO{sub 2}-exposure. At 4 weeks post-exposure, the histological features demonstrated that CeO{sub 2} induced lung phospholipidosis and fibrosis. DEP induced lung granulomas that were not significantly affected by the presence of CeO{sub 2} in the combined exposure. Using CeO{sub 2} as diesel fuel catalyst may cause health concerns. - Highlights: • DEP induced acute lung inflammation and switched immune response from Th1 to Th2. • DEP induced lung granulomas were not affected by the presence of CeO{sub 2}. • CeO{sub 2} induced sustained lung inflammation, phospholipidosis, and fibrosis. • After the combined exposure, CeO{sub 2} and DEP are co-localized in the lung tissues. • CeO{sub 2} + DEP induced lung inflammation, phospholipidosis, granulomas, and fibrosis.« less

Authors:
 [1]; ; ; ;  [1];  [2];  [1]
  1. Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505 (United States)
  2. School of Pharmacy, West Virginia University, Morgantown, WV 26506 (United States)
Publication Date:
OSTI Identifier:
22439785
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 278; Journal Issue: 2; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ARGINASE; CATALYSTS; CERIUM OXIDES; COLLAGEN; CONCANAVALIN A; DIESEL FUELS; FIBROSIS; GRANULOMAS; INFLAMMATION; LUNGS; LYMPH NODES; LYMPHOCYTES; LYMPHOKINES; MACROPHAGES; NANOPARTICLES; PATHOGENS; PHOSPHOLIPIDS; RATS; SECRETION; TRANSMISSION ELECTRON MICROSCOPY

Citation Formats

Ma, Jane Y.C., E-mail: jym1@cdc.gov, Young, Shih-Houng, Mercer, Robert R., Barger, Mark, Schwegler-Berry, Diane, Ma, Joseph K., and Castranova, Vincent. Interactive effects of cerium oxide and diesel exhaust nanoparticles on inducing pulmonary fibrosis. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2014.04.019.
Ma, Jane Y.C., E-mail: jym1@cdc.gov, Young, Shih-Houng, Mercer, Robert R., Barger, Mark, Schwegler-Berry, Diane, Ma, Joseph K., & Castranova, Vincent. Interactive effects of cerium oxide and diesel exhaust nanoparticles on inducing pulmonary fibrosis. United States. doi:10.1016/J.TAAP.2014.04.019.
Ma, Jane Y.C., E-mail: jym1@cdc.gov, Young, Shih-Houng, Mercer, Robert R., Barger, Mark, Schwegler-Berry, Diane, Ma, Joseph K., and Castranova, Vincent. Tue . "Interactive effects of cerium oxide and diesel exhaust nanoparticles on inducing pulmonary fibrosis". United States. doi:10.1016/J.TAAP.2014.04.019.
@article{osti_22439785,
title = {Interactive effects of cerium oxide and diesel exhaust nanoparticles on inducing pulmonary fibrosis},
author = {Ma, Jane Y.C., E-mail: jym1@cdc.gov and Young, Shih-Houng and Mercer, Robert R. and Barger, Mark and Schwegler-Berry, Diane and Ma, Joseph K. and Castranova, Vincent},
abstractNote = {Cerium compounds have been used as a fuel-borne catalyst to lower the generation of diesel exhaust particles (DEPs), but are emitted as cerium oxide nanoparticles (CeO{sub 2}) along with DEP in the diesel exhaust. The present study investigates the effects of the combined exposure to DEP and CeO{sub 2} on the pulmonary system in a rat model. Specific pathogen-free male Sprague–Dawley rats were exposed to CeO{sub 2} and/or DEP via a single intratracheal instillation and were sacrificed at various time points post-exposure. This investigation demonstrated that CeO{sub 2} induces a sustained inflammatory response, whereas DEP elicits a switch of the pulmonary immune response from Th1 to Th2. Both CeO{sub 2} and DEP activated AM and lymphocyte secretion of the proinflammatory cytokines IL-12 and IFN-γ, respectively. However, only DEP enhanced the anti-inflammatory cytokine IL-10 production in response to ex vivo LPS or Concanavalin A challenge that was not affected by the presence of CeO{sub 2}, suggesting that DEP suppresses host defense capability by inducing the Th2 immunity. The micrographs of lymph nodes show that the particle clumps in DEP + CeO{sub 2} were significantly larger than CeO{sub 2} or DEP, exhibiting dense clumps continuous throughout the lymph nodes. Morphometric analysis demonstrates that the localization of collagen in the lung tissue after DEP + CeO{sub 2} reflects the combination of DEP-exposure plus CeO{sub 2}-exposure. At 4 weeks post-exposure, the histological features demonstrated that CeO{sub 2} induced lung phospholipidosis and fibrosis. DEP induced lung granulomas that were not significantly affected by the presence of CeO{sub 2} in the combined exposure. Using CeO{sub 2} as diesel fuel catalyst may cause health concerns. - Highlights: • DEP induced acute lung inflammation and switched immune response from Th1 to Th2. • DEP induced lung granulomas were not affected by the presence of CeO{sub 2}. • CeO{sub 2} induced sustained lung inflammation, phospholipidosis, and fibrosis. • After the combined exposure, CeO{sub 2} and DEP are co-localized in the lung tissues. • CeO{sub 2} + DEP induced lung inflammation, phospholipidosis, granulomas, and fibrosis.},
doi = {10.1016/J.TAAP.2014.04.019},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 278,
place = {United States},
year = {Tue Jul 15 00:00:00 EDT 2014},
month = {Tue Jul 15 00:00:00 EDT 2014}
}
  • Background: Cerium oxide (CeO{sub 2}) nanoparticles improve the burning efficiency of fuel, however, little is known about health impacts of altered emissions from the vehicles. Methods: Atherosclerosis-prone apolipoprotein E knockout (ApoE{sup -/-}) mice were exposed by inhalation to diluted exhaust (1.7 mg/m{sup 3}, 20, 60 or 180 min, 5 day/week, for 4 weeks), from an engine using standard diesel fuel (DE) or the same diesel fuel containing 9 ppm cerium oxide nanoparticles (DCeE). Changes in hematological indices, clinical chemistry, atherosclerotic burden, tissue levels of inflammatory cytokines and pathology of the major organs were assessed. Results: Addition of CeO{sub 2} tomore » fuel resulted in a reduction of the number (30%) and surface area (10%) of the particles in the exhaust, whereas the gaseous co-pollutants were increased (6-8%). There was, however, a trend towards an increased size and complexity of the atherosclerotic plaques following DE exposure, which was not evident in the DCeE group. There were no clear signs of altered hematological or pathological changes induced by either treatment. However, levels of proinflammatory cytokines were modulated in a brain region and liver following DCeE exposure. Conclusions: These results imply that addition of CeO{sub 2} nanoparticles to fuel decreases the number of particles in exhaust and may reduce atherosclerotic burden associated with exposure to standard diesel fuel. From the extensive assessment of biological parameters performed, the only concerning effect of cerium addition was a slightly raised level of cytokines in a region of the central nervous system. Overall, the use of cerium as a fuel additive may be a potentially useful way to limit the health effects of vehicle exhaust. However, further testing is required to ensure that such an approach is not associated with a chronic inflammatory response which may eventually cause long-term health effects.« less
  • 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{sub 2}) nanoparticles in the diesel exhaust. In a previous study, we have demonstrated a wide range of CeO{sub 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{sub 2} in a rat model at various time points up to 84 days post-exposure. Male Sprague Dawley rats were exposed to CeO{sub 2} by a single intratracheal instillation. Alveolar macrophagesmore » (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{sub 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{sub 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 3.5 mg/kg CeO{sub 2} and euthanized at 28 days post-exposure. Collectively, our studies show that CeO{sub 2} induced fibrotic lung injury in rats, suggesting it may cause potential health effects. -- Highlights: ► Cerium oxide exposure significantly affected the following parameters in the lung. ► Induced fibrotic cytokine OPN and TGF-β1 production and phospholipidosis. ► Caused imbalance of the MMP-9/ TIMP-1 ratio that favors fibrosis. ► Cerium oxide particles were detected in lung tissue and AM. ► Cerium oxide caused lung fibrosis in a dose- and time-dependent manner.« less
  • Recently cerium compounds have been used in a variety of consumer products, including diesel fuel additives, to increase fuel combustion efficiency and decrease diesel soot emissions. However, cerium oxide (CeO{sub 2}) nanoparticles have been detected in the exhaust, which raises a health concern. Previous studies have shown that exposure of rats to nanoscale CeO{sub 2} by intratracheal instillation (IT) induces sustained pulmonary inflammation and fibrosis. In the present study, male Sprague–Dawley rats were exposed to CeO{sub 2} or CeO{sub 2} coated with a nano layer of amorphous SiO{sub 2} (aSiO{sub 2}/CeO{sub 2}) by a single IT and sacrificed at variousmore » times post-exposure to assess potential protective effects of the aSiO{sub 2} coating. The first acellular bronchoalveolar lavage (BAL) fluid and BAL cells were collected and analyzed from all exposed animals. At the low dose (0.15 mg/kg), CeO{sub 2} but not aSiO{sub 2}/CeO{sub 2} exposure induced inflammation. However, at the higher doses, both particles induced a dose-related inflammation, cytotoxicity, inflammatory cytokines, matrix metalloproteinase (MMP)-9, and tissue inhibitor of MMP at 1 day post-exposure. Morphological analysis of lung showed an increased inflammation, surfactant and collagen fibers after CeO{sub 2} (high dose at 3.5 mg/kg) treatment at 28 days post-exposure. aSiO{sub 2} coating significantly reduced CeO{sub 2}-induced inflammatory responses in the airspace and appeared to attenuate phospholipidosis and fibrosis. Energy dispersive X-ray spectroscopy analysis showed Ce and phosphorous (P) in all particle-exposed lungs, whereas Si was only detected in aSiO{sub 2}/CeO{sub 2}-exposed lungs up to 3 days after exposure, suggesting that aSiO{sub 2} dissolved off the CeO{sub 2} core, and some of the CeO{sub 2} was transformed to CePO{sub 4} with time. These results demonstrate that aSiO{sub 2} coating reduce CeO{sub 2}-induced inflammation, phospholipidosis and fibrosis. - Highlights: • Both CeO{sub 2} and aSiO{sub 2}/CeO{sub 2} particles were detected in the respective particle-exposed lungs. • The dissolution of aSiO{sub 2} coating from CeO{sub 2} particle core with time was demonstrated in the particle-exposed lungs. • aSiO{sub 2} coating significantly protected CeO{sub 2}-induced pulmonary inflammatory responses. • aSiO{sub 2} coating showed a protective effect on CeO{sub 2}-induced lung fibrosis.« less
  • The emission of cerium oxide nanoparticles (CeO{sub 2}) from diesel engines, using cerium compounds as a catalyst to lower the diesel exhaust particles, is a health concern. We have previously shown that CeO{sub 2} induced pulmonary inflammation and lung fibrosis. The objective of the present study was to investigate the modification of fibroblast function and the role of epithelial-mesenchymal transition (EMT) in CeO{sub 2}-induced fibrosis. Male Sprague-Dawley rats were exposed to CeO{sub 2} (0.15 to 7 mg/kg) by a single intratracheal instillation and sacrificed at various times post-exposure. The results show that at 28 days after CeO{sub 2} (3.5 mg/kg)more » exposure, lung fibrosis was evidenced by increased soluble collagen in bronchoalveolar lavage fluid, elevated hydroxyproline content in lung tissues, and enhanced sirius red staining for collagen in the lung tissue. Lung fibroblasts and alveolar type II (ATII) cells isolated from CeO{sub 2}-exposed rats at 28 days post-exposure demonstrated decreasing proliferation rate when compare to the controls. CeO{sub 2} exposure was cytotoxic and altered cell function as demonstrated by fibroblast apoptosis and aggregation, and ATII cell hypertrophy and hyperplasia with increased surfactant. The presence of stress fibers, expressed as α-smooth muscle actin (SMA), in CeO{sub 2}-exposed fibroblasts and ATII cells was significantly increased compared to the control. Immunohistofluorescence analysis demonstrated co-localization of TGF-β or α-SMA with prosurfactant protein C (SPC)-stained ATII cells. These results demonstrate that CeO{sub 2} exposure affects fibroblast function and induces EMT in ATII cells that play a role in lung fibrosis. These findings suggest potential adverse health effects in response to CeO{sub 2} nanoparticle exposure. - Highlights: • CeO{sub 2} exposure induced lung fibrosis. • CeO{sub 2} were detected in lung tissue, alveolar type II (ATII) cells and fibroblasts. • CeO{sub 2} caused ATII cell hypertrophy and hyperplasia and altered fibroblast function. • Increased α-SMA in CeO{sub 2}-exposed lung fibroblasts indicating myofibroblast formation. • CeO{sub 2} induced EMT in ATII cells demonstrated as increased α-SMA expression.« less
  • The in vivo effects of inhalation of diesel engine exhaust (DEE) on pulmonary alveolar macrophages (PAM) was studied in 73 guinea pigs and 48 rats. Animals were exposed in individual cages in special chambers to 3 different dose levels of DEE expressed in terms of the concentration of soot or carbon particles (-P); 250, 1500, 6000 micrograms DEE-P/M3. Exposure durations for guinea pigs were 1 and 3 days, 1 and 2 weeks, 2, 4, 8 and 12 months while rats were exposed 1, 2, 4, 8 and 12 months. Age matched controls were similarly exposed concurrently to clean air. PAMmore » obtained by bronchopulmonary lavage from exposed animals had viabilities comparable to controls. PAM diameters and relative surface areas increased 2 to 3 fold over controls and in relation to both the dose of DEE-P given and the exposure duration. Most of the in vivo exposed PAM had phagocytized DEE-P which did not appear to be cytotoxic and remained confined in phagosomes as discrete particles with diameters of 0.014 to 0.072 micrometer. Ability of PAM to adhere and spread on test surfaces was greater in the DEE-P sets than in controls. DEE-P containing PAM were still able to phagocytize latex particles when fed in vitro. However, such PAM had defective phagocytosis ability, and did not in the same time interval take up as much fluorescent latex as controls when studied by flow system technology. Absolute numbers of PAM in guinea pig lavages from exposures to 250 and 1500 microgram DEE-P/M3 for 2 months were not significantly changed over concurrent controls. Exudative leukocytes (eosinophils in guinea pigs and neutrophils in rats) appeared in the lavage in greater numbers as dose and duration of exposure increased. Another species difference was the appearance in DEE-P exposed guinea pig lavages of reactive monocytes.« less