Nanoparticle Exposure Driven Circulating Bioactive Peptidome Causes Systemic Inflammation and Vascular Dysfunction

Details

• Personal Author:
  Bishop L ; Campen MJ ; Canal CG ; Erdely A ; Mostovenko E ; Muldoon PP ; Ottens AK ; Vucetic A ; Young T ; Zeidler-Erdely PC
• Description:
  BACKGROUND: The mechanisms driving systemic effects consequent pulmonary nanoparticle exposure remain unclear. Recent work has established the existence of an indirect process by which factors released from the lung into the circulation promote systemic inflammation and cellular dysfunction, particularly on the vasculature. However, the composition of circulating contributing factors and how they are produced remains unknown. Evidence suggests matrix protease involvement; thus, here we used a well-characterized multi-walled carbon nanotube (MWCNT) oropharyngeal aspiration model with known vascular effects to assess the distinct contribution of nanoparticle-induced peptide fragments in driving systemic pathobiology. RESULTS: Data-independent mass spectrometry enabled the unbiased quantitative characterization of 841 significant MWCNT-responses within an enriched peptide fraction, with 567 of these factors demonstrating significant correlation across animal-paired bronchoalveolar lavage and serum biofluids. A database search curated for known matrix protease substrates and predicted signaling motifs enabled identification of 73 MWCNT-responsive peptides, which were significantly associated with an abnormal cardiovascular phenotype, extracellular matrix organization, immune-inflammatory processes, cell receptor signaling, and a MWCNT-altered serum exosome population. Production of a diverse peptidomic response was supported by a wide number of upregulated matrix and lysosomal proteases in the lung after MWCNT exposure. The peptide fraction was then found bioactive, producing endothelial cell inflammation and vascular dysfunction ex vivo akin to that induced with whole serum. Results implicate receptor ligand functionality in driving systemic effects, exemplified by an identified 59-mer thrombospondin fragment, replete with CD36 modulatory motifs, that when synthesized produced an anti-angiogenic response in vitro matching that of the peptide fraction. Other identified peptides point to integrin ligand functionality and more broadly to a diversity of receptor-mediated bioactivity induced by the peptidomic response to nanoparticle exposure. CONCLUSION: The present study demonstrates that pulmonary-sequestered nanoparticles, such as multi-walled carbon nanotubes, acutely upregulate a diverse profile of matrix proteases, and induce a complex peptidomic response across lung and blood compartments. The serum peptide fraction, having cell-surface receptor ligand properties, conveys peripheral bioactivity in promoting endothelial cell inflammation, vasodilatory dysfunction and inhibiting angiogenesis. Results here establish peptide fragments as indirect, non-cytokine mediators and putative biomarkers of systemic health outcomes from nanoparticle exposure. [Description provided by NIOSH]
• Subjects:
  Blood Environmental Exposure Lung Lung Diseases Occupational Health Respiratory System Respiratory Tract Diseases Risk Assessment Risk Factors Safety
• Keywords:
  Author Keywords: Carbon Nanotubes Blood Serum Cardiovascular Function Endothelial Cells Exposure Levels Inflammation Lung Disorders Mass Spectrometry MMP Multi-walled Carbon Nanotubes MWCNT Nanomaterial Nanomaterials Nanoparticles Nanotechnology Peptides Peptidome Pulmonary System Disorders Respiratory System Disorders Risk Factors Thrombospondin Vascular Dysfunction

  More +
• ISSN:
  1743-8977
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  New Mexico ; OSHA Region 3 ; OSHA Region 6 ; 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:
  20
• Volume:
  16
• NIOSHTIC Number:
  nn:20056044
• Citation:
  Part Fibre Toxicol 2019 May; 16:20
• Contact Point Address:
  Andrew K. Ottens, Department of Anatomy and Neurobiology, Virginia Commonwealth University, Box 980709, Richmond, VA 23298-0709, USA
• Email:
  akottens@vcu.edu
• CAS Registry Number:
  Carbon nanotubes (CAS RN 308068-56-6)
• Federal Fiscal Year:
  2019
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of New Mexico Health Sciences Center, Albuquerque, New Mexico
• Peer Reviewed:
  True
• Start Date:
  20130901
• Source Full Name:
  Particle and Fibre Toxicology
• End Date:
  20150831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:9ce77b004445b552f58bf3278e4460828034bcaaad74dcd95980519f2a8aaf5a151e47581ac38b580e0fb965b95497c5bfd1380e84498d93692b3ad91e752e84
• Download URL:
  https://stacks.cdc.gov/view/cdc/213741/cdc_213741_DS1.pdf
• File Type:
  [PDF - 2.51 MB ]