Abstract
BackgroundThe 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.ResultsData-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.ConclusionThe 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.
Highlights
The mechanisms driving systemic effects consequent pulmonary nanoparticle exposure remain unclear
Systemic inflammation [9], atherosclerosis [10], vascular dysfunction [11], and even cognitive deficits [12] have been reported from multi-walled carbon nanotube (MWCNT) pulmonary exposure, impacting other organ systems such as the liver, kidneys [13] and brain [14]
More than half of the bronchoalveolar lavage fluid (BALF)-serum common measures (872 of the 1712) were exclusively detected either among replicate specimens from MWCNT or dispersion media (DM) vehicle treatment groups, 613 (70%) of those solely detected after MWCNT exposure
Summary
The mechanisms driving systemic effects consequent pulmonary nanoparticle exposure remain unclear. Evidence suggests matrix protease involvement; 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. The health implications of environmental or occupational nanoscale particulate extend well beyond the lung, with inflammation and dysfunction evident after exposure in the cardiovasculature and other organs like the brain [4,5,6,7]. Cardiovascular deficits from nanoparticle exposure have been reported without pulmonary inflammation [20, 21] This suggests that extra-pulmonary outcomes are mediated by as-yet-unknown, non-cytokine, bioactive molecules released into the circulation [22, 23]
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