Multiwalled carbon nanotubes induce a fibrogenic response by stimulating reactive oxygen species production, activating NF-kB signaling, and promoting fibroblast-to-myofibroblast transformation

Details

• Personal Author:
  Chisholm WP ; Fernback, Joseph E. ; He X ; Ma Q ; Schwegler-Berry DE ; Young S-H
• Description:
  Carbon nanotubes (CNTs) are novel materials with unique electronic and mechanical properties. The extremely small size, fiberlike shape, large surface area, and unique surface chemistry render their distinctive chemical and physical characteristics and raise potential hazards to humans. Several reports have shown that pulmonary exposure to CNTs caused inflammation and lung fibrosis in rodents. The molecular mechanisms that govern CNT lung toxicity remain largely unaddressed. Here, we report that multiwalled carbon nanotubes (MWCNTs) have potent, dose-dependent toxicity on cultured human lung cells (BEAS-2B, A549, and WI38-VA13). Mechanistic analyses were carried out at subtoxic doses (≤20 µg/mL, ≤ 24 h). MWCNTs induced substantial ROS production and mitochondrial damage, implicating oxidative stress in cellular damage by MWCNT. MWCNTs activated the NF-kB signaling pathway in macrophages (RAW264.7) to increase the secretion of a panel of cytokines and chemokines (TNFa, IL-1β, IL-6, IL-10, and MCP1) that promote inflammation. Activation of NF-kB involved rapid degradation of IkBa, nuclear accumulation of NF-kBp65, binding of NF-kB to specific DNA-binding sequences, and transactivation of target gene promoters. Finally, MWCNTs induced the production of profibrogenic growth factors TGFβ1 and PDGF from macrophages that function as paracrine signals to promote the transformation of lung fibroblasts (WI38-VA13) into myofibroblasts, a key step in the development of fibrosis. Our results revealed that MWCNTs elicit multiple and intertwining signaling events involving oxidative damage, inflammatory cytokine production, and myofibroblast transformation, which potentially underlie the toxicity and fibrosis in human lungs by MWCNTs. [Description provided by NIOSH]
• Subjects:
  Cytotoxins DNA Genetics Hazardous Substances Immune System Lung Lung Diseases Occupational Health Particulate Matter Respiratory System Respiratory Tract Diseases Safety

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• Keywords:
  Cell-damage Cell-function Cytotoxic-effects DNA-damage Dose-response Fiber-deposition Genes Genotoxic-effects Hazardous-materials Immune-reaction Lung-cells Lung-disorders Lung-fibrosis Lung-irritants Nanotechnology Oxidative-processes Pulmonary-system Pulmonary-system-disorders Respiratory-system-disorders Toxic-dose Toxic-effects Toxic-materials

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• ISSN:
  0893-228X
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Ohio ; OSHA Region 3 ; OSHA Region 5 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division ; DART - Division of Applied Research and Technology
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  24
• Issue:
  12
• NIOSHTIC Number:
  nn:20040058
• Citation:
  Chem Res Toxicol 2011 Dec; 24(12):2237-2248
• Contact Point Address:
  Xiaoqing He, Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505, USA
• Email:
  qam1@cdc.gov
• CAS Registry Number:
  Carbon (CAS RN 7440-44-0)
• Federal Fiscal Year:
  2012
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Chemical Research in Toxicology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:b4ed940500d4ebe80165107b63ea97a87f0918604c6f67371261f50ca45f0e0eea3a28826503f415663a4b364bdee37499329bedaa2b46a5fb0787bda4e46755
• Download URL:
  https://stacks.cdc.gov/view/cdc/193051/cdc_193051_DS1.pdf
• File Type:
  [PDF - 3.44 MB ]