The Role of Matrix Metalloproteinases in Multiwalled Carbon Nanotube (MWCNT)-Induced Inflammation in C57BL/6 Mice

Details

• Personal Author:
  Campen MJ ; Erdely AD ; Herbert G ; Lucas S ; Ottens AK ; Wang T ; Young TL
• Description:
  Matrix metalloproteinases (MMPs) are ubiquitously expressed extracellular matrix (ECM) proteases that are activated in inflammation and injury and play varied roles in cellular homeostasis, adaptation, tissue remodeling and immunity. We previously demonstrated that acute MWCNT exposure led to impaired vascular reactivity that was dependent on MMP-9 activation and CD36 signaling. We hypothesized that MWCNT inhalation exposure alters broad spectrum MMP activity, leading to serum-borne factors that enhance vascular permeability and activate inflammatory pathways. To test this hypothesis, male C57BL/6 mice (6-8 weeks) were given 10 mg/kg of the broad-spectrum MMP inhibitor, Marimastat, and then dosed with 0 (dispersion media; DM), 10 or 40 microg MWCNT via oropharyngeal aspiration 1 hour after Marimastat dosing. Pulmonary inflammation was evaluated 24 hrs following MWCNT exposure, in terms of cell and protein quantification of bronchoalveolar lavage fluid (BALF). Serum bioactivity was determined in mouse brain endothelial cells (MBEC) via serum cumulative inflammatory potential (SCIP) assay. Vascular integrity was evaluated via electric cell-substrate impedance sensing (ECIS) assay, and confocal assessment of intracellular gap formation. Neutrophil infiltration and total BALF protein significantly increased in 40 microg-dosed mice (n=6/group; p<0.01) and was not altered by MMP blockade. MBECs treated with serum from MWCNT-treated mice exhibited a approx. 75% reduction in barrier integrity compared to DM controls. A approx. 50% of DM recovery in barrier integrity was observed with MMP blockade. Additionally, MMP blockade diminished MWCNT serum-enhanced thrombin-mediated loss of barrier integrity and enhanced sphingosine 1-phosphate-induced barrier stability in MBEC. Actin immunostaining of MBEC confirmed that MWCNT serum exposure disrupted cell-cell junctions in a MMP-dependent manner. A thrombospondin type-1 domain-containing peptide reduced regrowth of MBECs in a dose-dependent manner (p<0.0001). Thus, while MMP blockade did not alter lung inflammation resulting from MWCNT exposure, subsequent pathologic serum bioactivity arising from MWCNT treatment was dependent on pulmonary MMP activity. [Description provided by NIOSH]
• Subjects:
  Biological Assay Blood Environmental Exposure Enzymes Immune System Laboratories Lung Occupational Health Pathology Respiratory System Safety Toxicology

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• Keywords:
  Antineoplastic Agents Bioassays Biological Effects Blood Serum Blood Vessels Carbon Nanotubes Cellular Effects Cellular Function Cellular Reactions CNT Dispersion Dose Response Endothelial Cells Exposure Assessment Exposure Levels Immune Reaction Inhalation Laboratory Animals Laboratory Testing Metalloproteins Multi-walled Carbon Nanotubes MWCNT Nanotoxicology Neutrophils Peptides Proteins Pulmonary Effects Serology

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Arizona ; California ; New Mexico ; OSHA Region 3 ; OSHA Region 6 ; OSHA Region 9 ; Virginia ; 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:
  46-47
• Volume:
  174
• Issue:
  1
• NIOSHTIC Number:
  nn:20058869
• Citation:
  Toxicologist 2020 Mar; 174(1):46-47
• CAS Registry Number:
  Carbon nanotubes (CAS RN 308068-56-6)
• Federal Fiscal Year:
  2020
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 59th Annual Meeting and ToxExpo, March 15-19, 2020, Anaheim, California
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:df08a7220d7075837ef5c45875114ea0f3bf78e2301483db24e51a82050062c0a08acd8e07923d60d8184973d9dde5db2847d64862025974e06d1f16df067a1f
• Download URL:
  https://stacks.cdc.gov/view/cdc/223244/cdc_223244_DS1.pdf
• File Type:
  [PDF - 539.13 KB ]