Mediation of the Single-Walled Carbon Nanotubes Induced Pulmonary Fibrogenic Response by Osteopontin and TGF-beta1

Details

• Personal Author:
  Fatkhutdinova LM ; Gutkin DW ; Kagan VE ; Khaliullin TO ; Kisin ER ; Murray AR ; Shurin MR ; Shvedova AA ; Yanamala N
• Description:
  Purpose of the study: A number of in vivo studies have shown that pulmonary exposure to carbon nanotubes (CNTs) may lead to an acute local inflammatory response, pulmonary fibrosis, and granulomatous lesions. Among the factors that play direct roles in initiation and progression of fibrotic processes are epithelial-mesenchymal transition and myofibroblasts recruitment/differentiation, both mediated by transforming growth factor-beta1 (TGF-beta1). Yet, other contributors to TGF-beta1 associated signaling, such as osteopontin (OPN) has not been fully investigated. Materials and Methods: 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 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. Results and Conclusions: Diminished lactate dehydrogenase activity at all time points, along with less pronounced neutrophil influx 24 h post-exposure, were measured in broncho-alveolar lavage (BAL) of OPN-KO mice compared to WT. Pro-inflammatory cytokine release (IL-6, TNF-alpha, MCP-1) was reduced. A significant two-fold increase of TGF-beta1 was found in BAL of WT mice at 7 days, while TGF-beta1 levels in OPN-KO animals remained unaltered. Histological examination revealed marked decrease in granuloma formation and less collagen deposition in the lungs of OPN-KO mice compared to WT. RAW 264.7 but not MLE-15 cells exposed to SWCNT and bleomycin had significantly less TGF-beta1 released in the presence of OPN-blocking antibody. We believe that OPN is important in initiating the cellular mechanisms that produce an overall pathological response to SWCNT and it may act upstream of TGF-beta1. Further investigation to understand the mechanistic details of such interactions is critical to predict outcomes of pulmonary exposure to CNT. [Description provided by NIOSH]
• Subjects:
  Immune System Laboratories Lung Lung Diseases Occupational Health Respiratory System Respiratory Tract Diseases Safety Toxicology
• Keywords:
  Author Keywords: Carbon Nanotubes Cytokines Fibrogenicity Immune Reaction Laboratory Animals Lung Fibrosis Nanotoxicology Neutrophils Osteopontin Pulmonary Effects Pulmonary Exposure Single-walled Carbon Nanotubes SWCNT TGF-beta1

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• ISSN:
  0190-2148
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  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
• Pages in Document:
  311-326
• Volume:
  43
• Issue:
  8
• NIOSHTIC Number:
  nn:20050796
• Citation:
  Exp Lung Res 2017 Oct; 43(8):311-326
• Contact Point Address:
  Dr. Anna A. Shvedova, CDC/NIOSH/HELD, Exposure Assessment Branch, 1095 Willowdale Road, Morgantown, WV 26505 USA
• Email:
  ats1@cdc.gov
• CAS Registry Number:
  Carbon nanotubes (CAS RN 308068-56-6)
• Federal Fiscal Year:
  2018
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Experimental Lung Research
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:4748e7fcf0b74199bd561672db9e2238605e09bf6074ddf1c9e57b3aed03fd37bed7b2c66b6c1c591694f7c83fee928695d5cf5da7ee86987de546018e4dd287
• Download URL:
  https://stacks.cdc.gov/view/cdc/211009/cdc_211009_DS1.pdf
• File Type:
  [PDF - 1.68 MB ]