Osteopontin modulates SWCNT-induced pulmonary fibrosis upstream of the TGF-beta1 signaling

Details

• Personal Author:
  Kagan VE ; Khaliullin TO ; Kisin ER ; Shurin MR ; Shvedova AA ; Yanamala N
• Description:
  It has been shown by a number of in vivo studies that pulmonary exposure to carbon nanotubes may lead to acute local inflammatory response, pulmonary fibrosis and granulomatous lesions. Among factors that play direct role in initiation and progression of fibrotic process are epithelial-mesenchymal transition and myofibroblasts recruitment/differentiation, mediated by the transforming growth factor-beta1 (TGF-beta1). Yet, other contributors to the TGF-beta1 associated signaling, such as osteopontin (OPN) has not been fully investigated. To explore this issue, OPN-knockout female mice (OPN-KO) along with their wild-type (WT) counterparts were exposed to single-walled carbon nanotubes (SWCNT) (40 microg/mouse) via pharyngeal aspiration and pulmonary fibrotic response was assessed 1, 7 and 28 days post-exposure. Simultaneously, RAW 264.7 and MLE-15 cells were treated with SWCNT (24 hours, 6 microg/cm2 to 48 microg/cm2) or bleomycin (0.1 microg/ml) in the presence of OPN-blocking antibody or isotype control and TGF-beta1 was measured in supernatants. Diminished lactate dehydrogenase activity and protein levels at all time points, along with less pronounced neutrophil influx 24 h post-exposure, were registered in broncho-alveolar lavage fluid (BALF) of OPN-KO mice compared to WT mice. Pro-inflammatory cytokines release (IL-6, TNF-alpha, MCP-1) was also reduced. A significant two-fold increase in TGF-beta1 was found in BALF of WT mice at 7 days, while TGF-beta1 levels in OPN-KO animals remained unaltered. Histological examination revealed marked decrease in granulomas formation and less collagen deposition in the lungs of OPN-KO mice compared to WT. RAW 264.7 and MLE-15 cells exposed to SWCNT and bleomycin had significantly less TGF-beta1 released in the presence of OPN-blocking antibody. Thus, we believe that OPN is important in initiating the cellular mechanisms that produce an overall pathological response to SWCNT and it acts upstream of TGF-beta1. Further investigation to understand the mechanistic details of such interactions is critical to predict outcomes produced by carbon nanotubes pulmonary exposure. [Description provided by NIOSH]
• Subjects:
  Anti-Bacterial Agents Antibodies Blood Body Fluids Fibrosis Growth Immune System Laboratories Lung Lung Diseases Occupational Health Respiratory System Respiratory Tract Diseases Safety Toxicology

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• Keywords:
  Antibiotics Body Fluids Carbon Nanotubes Cell Metabolism Cell Signaling Cellular Effects Cellular Reactions Cytokines Enzymatic Effects Exposure Assessment Fibrogenicity Growth Factors Immune Reaction Immune System Laboratory Animals Laboratory Testing Lung Cells Lung Fibrosis Lymphocytes Nanotechnology Nanotoxicology Nanotubes Neutrophils Peptides Proteins Pulmonary Effects Pulmonary System Disorders Respiratory System Disorders Single-walled Carbon Nanotubes SWCNT

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Maryland ; OSHA Region 3 ; Pennsylvania ; 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:20049467
• Citation:
  Toxicologist 2017 Mar; 156(1):403
• CAS Registry Number:
  Bleomycin (CAS RN 11056-06-7) ; Carbon nanotubes (CAS RN 308068-56-6) ; Osteopontin (rat clone λROP11 protein moiety) (CAS RN 106441-73-0)
• Federal Fiscal Year:
  2017
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 56th Annual Meeting and ToxExpo, March 12-16, 2017, Baltimore, Maryland
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:18009fce30766d8fbe8889b9ab2888ffaf756cf8a345dfdd18de51098cd0f2ad6ed7cd95e6e31eabc2eb650f3805eaac1f1a40b005aa1165be27912c32905191
• Download URL:
  https://stacks.cdc.gov/view/cdc/203911/cdc_203911_DS1.pdf
• File Type:
  [PDF - 944.27 KB ]