Pulmonary Delivery of the Broad-Spectrum Matrix Metalloproteinase Inhibitor Marimastat Diminishes Multiwalled Carbon Nanotube-Induced Circulating Bioactivity Without Reducing Pulmonary Inflammation

Details

• Personal Author:
  Begay JG ; Campen MJ ; Denson JL ; Erdely A ; Fraser K ; Herbert G ; Hunter R ; Lucas SN ; Mostovenko E ; Ottens AK ; Salazar R ; Wang T ; Young TL ; Zychowski K
• Description:
  Background: Multiwalled carbon nanotubes (MWCNT) are an increasingly utilized engineered nanomaterial that pose the potential for significant risk of exposure-related health outcomes. The mechanism(s) underlying MWCNT-induced toxicity to extrapulmonary sites are still being defined. MWCNT-induced serum-borne bioactivity appears to dysregulate systemic endothelial cell function. The serum compositional changes after MWCNT exposure have been identified as a surge of fragmented endogenous peptides, likely derived from matrix metalloproteinase (MMP) activity. In the present study, we utilize a broad-spectrum MMP inhibitor, Marimastat, along with a previously described oropharyngeal aspiration model of MWCNT administration to investigate the role of MMPs in MWCNT-derived serum peptide generation and endothelial bioactivity. Results: C57BL/6 mice were treated with Marimastat or vehicle by oropharyngeal aspiration 1 h prior to MWCNT treatment. Pulmonary neutrophil infiltration and total bronchoalveolar lavage fluid protein increased independent of MMP blockade. The lung cytokine profile similarly increased following MWCNT exposure for major inflammatory markers (IL-1beta, IL-6, and TNF-alpha), with minimal impact from MMP inhibition. However, serum peptidomic analysis revealed differential peptide compositional profiles, with MMP blockade abrogating MWCNT-derived serum peptide fragments. The serum, in turn, exhibited differential potency in terms of inflammatory bioactivity when incubated with primary murine cerebrovascular endothelial cells. Serum from MWCNT-treated mice led to inflammatory responses in endothelial cells that were significantly blunted with serum from Marimastat-treated mice. Conclusions: Thus, MWCNT exposure induced pulmonary inflammation that was largely independent of MMP activity but generated circulating bioactive peptides through predominantly MMP-dependent pathways. This MWCNT-induced lung-derived bioactivity caused pathological consequences of endothelial inflammation and barrier disruption. [Description provided by NIOSH]
• Subjects:
  Biomarkers Laboratories Lung Occupational Health Respiratory System Safety Toxicology
• Keywords:
  Author Keywords: Multiwall Carbon Nanotube Bioactivation Biomarker Carbon Nanotubes Cytokines Infammation Laboratory Animals Matrix Metalloproteinase Multi-walled Carbon Nanotubes MWCNT Nanomaterials Nanoparticles Nanotoxicology Neutrophils Pulmonary Effects Serum-bioactivity

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• ISSN:
  1743-8977
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Arizona ; 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:
  34
• Volume:
  18
• NIOSHTIC Number:
  nn:20063470
• Citation:
  Part Fibre Toxicol 2021 Sep; 18:34
• Contact Point Address:
  Matthew J. Campen, Department of Pharmaceutical Sciences, MSC09 5360, 1 University of New Mexico, Albuquerque, NM 87131-0001, USA
• Email:
  MCampen@salud.unm.edu
• CAS Registry Number:
  Carbon nanotubes (CAS RN 308068-56-6)
• Federal Fiscal Year:
  2021
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of New Mexico Health Sciences Center, Albuquerque, New Mexico
• Peer Reviewed:
  True
• Start Date:
  20150930
• Source Full Name:
  Particle and Fibre Toxicology
• End Date:
  20190929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:15c6b3caf53f8d3537bfe4110c6af3c4bfea7248b659ee1e816c2b9d6ab11d11204bff3e43cb88aa265459a374950042bd66fc23fbfc7db9afaccb7444071769
• Download URL:
  https://stacks.cdc.gov/view/cdc/226532/cdc_226532_DS1.pdf
• File Type:
  [PDF - 2.65 MB ]