Identification of TGF-beta receptor-1 as a key regulator of carbon nanotube-induced fibrogenesis

Details

• Personal Author:
  Castranova, Vincent ; Derk R ; Mercer RR ; Mishra A ; Rojanasakul Y ; Stueckle, Todd A. ; Wang L
• Description:
  Carbon nanotubes (CNTs) induce rapid interstitial lung fibrosis, but the underlying mechanisms are unclear. Previous studies indicated that the ability of CNTs to penetrate lung epithelium, enter interstitial tissue, and stimulate fibroblasts to produce collagen matrix is important to lung fibrosis. In this study, we investigated the activation of transforming growth factor-beta receptor-1 [TGF-Beta R1; i.e., activin receptor-like kinase 5 (ALK5) receptor] and TGF-Beta/Smad signaling pathway in CNT-induced collagen production in human lung fibroblasts. Human lung fibroblasts and epithelial cells were exposed to low, physiologically relevant concentrations (0.02-0.6 microg/cm2) of single-walled CNTs (SWCNT) and multiwalled CNTs (MWCNT) in culture and analyzed for collagen, TGF-Beta1, TGF-Beta R1, and SMAD proteins by Western blotting and immunofluorescence. Chemical inhibition of ALK5 and short-hairpin (sh) RNA targeting of TGF-Beta R1 and Smad2 were used to probe the fibrogenic mechanism of CNTs. Both SWCNT and MWCNT induced an overexpression of TGF-Beta1, TGF-Beta R1 and Smad2/3 proteins in lung fibroblasts compared with vehicle or ultrafine carbon black-exposed controls. SWCNT- and MWCNT-induced collagen production was blocked by ALK5 inhibitor or shRNA knockdown of TGF-Beta R1 and Smad2. Our results indicate the critical role of TGF-Beta R1/Smad2/3 signaling in CNT-induced fibrogenesis by upregulating collagen production in lung fibroblasts. This novel finding may aid in the design of mechanism-based risk assessment and development of rapid screening tests for nanomaterial fibrogenicity. [Description provided by NIOSH]
• Subjects:
  Cells, Cultured Environmental Monitoring Fibrosis Genetics Lung Lung Diseases Occupational Health Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  Author Keywords: Carbon Nanotubes Carbon-compounds Cell-cultures Cellular-function Chemical-inhibition Collagen-fibrils Collagen I Exposure-assessment Fibrogenesis Fibrogenicity Genes Humans Immunological-tests Lung Lung-disorders Lung-fibrosis Nanotechnology Proteins Pulmonary-system-disorders Receptor Respiratory-system-disorders Ribonucleic-acids Transforming Growth Factor

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• ISSN:
  1040-0605
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; 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:
  309
• Issue:
  8
• NIOSHTIC Number:
  nn:20046913
• Citation:
  Am J Physiol Lung Cell Mol Physiol 2015 Oct; 309(8):L821-L833
• Contact Point Address:
  L. Wang, HELD, National Institute for Occupational Safety and Health, Morgantown, WV 26505
• Email:
  lmw6@cdc.gov
• Federal Fiscal Year:
  2016
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  American Journal of Physiology: Lung Cellular and Molecular Physiology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:63545d4e0d6dbc18a34c4ba6db47da4ea827410540cb5a8240abe22b2fe999ac9199ad77b2c4d859eb669d4da0a9c3ad79883703d0a6e2162e3c111a83bab2a1
• Download URL:
  https://stacks.cdc.gov/view/cdc/202178/cdc_202178_DS1.pdf
• File Type:
  [PDF - 3.45 MB ]