Role of matrix metalloproteinases (MMPs) in multi-walled carbon nanotube (MWCNT) exposure-induced inflammatory responses

Details

• Personal Author:
  Aragon M ; Campen M ; Erdely A ; Ottens A ; Sanchez B ; Tyler C ; Young T
• Description:
  The mechanism by which MWCNT inhalation exposure causes extrapulmonary health effects is currently poorly understood. We recently demonstrated that MWCNT could generate circulating bioactivity that was dependent on MMP-9 and interactions between circulating ligands and the scavenger receptor/immunomodulator CD36, which ultimately led to endothelial dysfunction and impaired vasodilation. In the present study, we interrogated endothelial cell inflammatory responses and the potential for a major endogenous CD36 ligand, thrombospondin-1 (TSP- 1), to drive such systemic responses to pulmonary MWCNT exposure. We exposed C57BL/6 (WT) and MMP-9 (MMP-9-/-) knockout mice to 0 (dispersion media; DM), 10 or 40microg MWCNT via pharyngeal aspiration in an acute or repeated, subchronic exposure design. Acutely, mice were exposed once to 0, 10, or 40microg of MWCNT and euthanized 4 or 24h post-aspiration. For the subchronic exposure, mice were subjected to either one dose of 40microg MWCNT or DM, followed by weekly doses of DM; or once weekly doses of 10microg MWCNT and euthanized 4 weeks post initial aspiration. Bronchoalveolar lavage (BAL) fluid and serum MMP levels, serum TSP-1 and 4-hydroxy-2-nonenal (4HNE) (oxidative stress marker), and markers of neuroinflammation were evaluated via immunoblotting. MMP activity was assessed via zymography and vascular and neuroinflammatory gene expression were evaluated via qPCR. Acute 10microg MWCNT exposure resulted in a 90% increase in serum TSP-1 in WT mice compared to DM controls. No significant increase in TSP-1 was observed in MMP-9-/- mice with 4h MWCNT exposure. TSP-1 was increased 136% in MMP-9-/- and 94% in WT serum with repeated exposure to 10microg MWCNT compared to 57% and 24% respectively following a single 40microg MWCNT exposure. Serum 4HNE levels were unchanged by MWCNT exposure. Serum from both WT and MMP9-/- mice exhibited inflammatory bioactivity, however, suggesting that MMP9-cleaved ligands may drive vasodilatory impairments, but not endothelial inflammatory responses. These preliminary results suggest that MWCNT exposure induces serum TSP-1 in an MMP-9 independent manner, but it is unlikely that TSP-1 drives the cumulative circulating inflammatory potential induced by MWCNT. [Description provided by NIOSH]
• Subjects:
  Biomarkers Blood Body Fluids Cells, Cultured Immune System Laboratories Lung Occupational Exposure Occupational Health Respiratory System Safety Toxicology

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• Keywords:
  Acute Exposure Blood Serum Body Fluids Carbon Nanotubes Cell Cultures Dispersion Endothelial Cells Exposure Assessment Gene Expression Immune Reaction Immune System Immunoassays Inhalation Laboratory Animals Laboratory Testing Metalloproteins Multi-walled Carbon Nanotubes MWCNT Nanotechnology Nanotoxicology Nanotubes Neurological Reactions Oxidative Stress Proteins Pulmonary Effects Pulmonary System Serology

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• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Abstract or Summary
• Place as Subject:
  Maryland ; New Mexico ; OSHA Region 3 ; OSHA Region 6 ; Virginia ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  156
• Issue:
  1
• NIOSHTIC Number:
  nn:20049478
• Citation:
  Toxicologist 2017 Mar; 156(1):404
• CAS Registry Number:
  Carbon nanotubes (CAS RN 308068-56-6)
• Federal Fiscal Year:
  2017
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of New Mexico Health Sciences Center, Albuquerque, New Mexico
• Peer Reviewed:
  False
• Start Date:
  20150930
• Source Full Name:
  The Toxicologist. Society of Toxicology 56th Annual Meeting and ToxExpo, March 12-16, 2017, Baltimore, Maryland
• End Date:
  20190929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:e3a471cf75f2c8a0a35ede93d8c29aa922eac645888f86e14c029a78352023f20c4dff53c138d5c1f5ef50fb0912aabb6b4240ab2e340e1337fd69bf1785f898
• Download URL:
  https://stacks.cdc.gov/view/cdc/203920/cdc_203920_DS1.pdf
• File Type:
  [PDF - 945.09 KB ]