Lung Oxidative Stress/Inflammation by Carbon Nanotubes

Details

• Personal Author:
  Fabisiak J ; Kagan VE ; Ortiz L
• Description:
  Single Walled Carbon NanoTubes (SWCNT) are new materials of emerging technological importance. Universally broad applications of different nanomaterials, including SWCNT, has raised concerns about their safety and potential adverse health effects as well as undesirable impacts on the environment. Of particular import, may be pulmonary toxicity of SWCNT upon occupational exposures. Indeed, several studies have documented damaging effect of SWCNT on the lung realized through unusually robust inflammatory response accompanied by severe oxidative stress and leading to fibrosis. Unfortunately, specific mechanisms of SWCNT induced pulmonary toxicity are not known. The goal of the performed studies was to understand the pathways through which interaction of inflammation and oxidative stress is involved in deleterious pulmonary effects of SWCNT. Notably, the manufacturing of SWCNT requires large amounts of iron resulting in its high content in SWCNT. Because iron is a catalyst of oxidative stress, iron-containing SWCNT are likely more toxic than iron-free SWCNT. Our central hypothesis was that SWCNT are toxic to the lung and the toxicity is dependent on their content of iron. The major toxicity mechanisms include inflammatory response synergistically enhanced by oxidative stress exacerbated by iron. SWCNT toxic effects are further augmented by microbially-induced inflammation. The apoptotic/necrotic target cell death ratio dependent on the SWCNT iron is also a regulator of SWCNT toxicity via production of anti-/pro-inflammatory cytokines, respectively. We have successfully completed all specific aims of the project. Our studies pioneered the discovery of: 1) unusual inflammatory and fibrogenic pulmonary responses to SWCNT in mice in vivo; 2) the important role of transition metals, particularly iron, as enhancers of oxidative stress and inflammatory pulmonary responses to SWCNT, 3) essential nutritional (vitamin E status) and genetic (expression of NADPH oxidase) factors contributing to [pulmonary toxicity and 4) the fact of delayed bacterial clearance after SWCNT exposure likely associated with increased susceptibility to lung infection in exposed populations. There are three major approaches through which our completed studies can impact the safety and health issues in a specific workplace: 1) Establishment of new standards for occupational exposures to SWCNT (eg, Occupational Safety and Health Administration (OSHA) PEL for nanotubes). The maximum dose used in our published studies extrapolates to 20 days' exposure at the current OSHA standard for graphite. Our results suggest that there is significant toxicity at low exposure levels and those current regulations would not provide proper protection during occupational exposures at these levels to SWCNT. 2) Development of new biomarkers of pulmonary toxicity of SWCNT. Based on our studies of lipid peroxidation induced in the lung by SWCNT exposure, we initiated detailed mass-spectrometric studies of oxidized phospholipids as potential biomarkers. Further, a battery of pro-inflammatory and anti-inflammatory cytokines as they relate to the transition from acute inflammatory response to its chronic pro-fibrotic stage can be also utilized as biomarkers of SWCNT exposure. 3) Design of mechanism-based interventions, such as specific antioxidants, new chemical means to control the content of transition metals (using non-toxic chelators) as well as biotechnological approaches (liposomes containing specific signaling molecules) down-regulating inflammatory response. The signaling molecules may include phosphatidylserine (PS) acting as an "eat-me" recognition signal for professional phagocytes. We are confident that our studies are important for new strategies to decrease toxicity of (transition metal-containing) SWCNT. [Description provided by NIOSH]
• Subjects:
  Biomarkers Ferrous Compounds Fibrosis Immune System Lung Occupational Exposure Occupational Health Oxidants Respiratory System Safety Toxicology

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• Keywords:
  Biological Effects Carbon Nanotubes Cell Signaling Cellular Effects CNT Dose Response Graphite Immune Reaction Iron Nanomaterials Nanoparticles Nanotoxicology Occupational Exposure Oxidative Processes Pulmonary Effects

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• Series:
  Grant Final Reports
• Publisher:
  National Institute for Occupational Safety and Health
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Final Grant Report
• Place as Subject:
  OSHA Region 3 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  OEP - Office of Extramural Programs
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  1-22
• NIOSHTIC Number:
  nn:20053290
• NTIS Accession Number:
  PB2019-100251
• Citation:
  Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, R01-OH-008282, 2011 Feb; :1-22
• Contact Point Address:
  Valerian E. Kagan, PhD, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, PA 15219, USA
• Email:
  kagan@pitt.edu
• CAS Registry Number:
  Carbon nanotubes (CAS RN 308068-56-6) ; Graphite (CAS RN 7782-42-5) ; Iron (CAS RN 7439-89-6)
• Federal Fiscal Year:
  2011
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  False
• Start Date:
  20050701
• Source Full Name:
  National Institute for Occupational Safety and Health
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:7294cb6c14c3b1c772b4f586a434394cb218ffade705726bfbe137dde700b773333491fb72d8c60e2c1e58ff71f146fa6cda826d2c9f9e8cad208d8cbd09ffae
• Download URL:
  https://stacks.cdc.gov/view/cdc/218762/cdc_218762_DS1.pdf
• File Type:
  [PDF - 527.91 KB ]