Fig. 5
Peptide-mediated model of systemic bioactivation following pulmonary nanoparticle exposure. Results from this study support a proposed paradigm (a) by which nanoparticles in the lung activate matrix proteases, with a diversity of generated peptide products released into circulation with some acting as cell-surface receptor ligands that drive systemic vascular dysfunction and inflammation. The model depicts peptides products of thrombospondin and integrin-ligand proteins from the MWCNT-responsive peptidome triggering CD36 and integrin receptor signaling with downstream anti-angiogenic and inflammatory marker outcomes. b Following synthesis of the identified MWCNT-responsive TSP402–460 peptide, its anti-angiogenic properties were assessed using an electronic wound-healing assay after a 4-h treatment. c Likewise, the electronic wound-healing assay was used to assess the anti-angiogenic properties after a 4-h treatment with the serum peptide fraction from n = 6 MWCNT treated animals per dose. Electrical impedance values were plotted per hour for 10 h following wounding, with data centered and normalized as a percentage of pretreatment impedance and given as mean ± SE, n = 6 in vitro replicates, *p < 0.05. d Peptides identified from known integrin-binding proteins were dose-dependently increased, mass spectral intensity normalized as a % of DM vehicle control presented as mean ± SE, n = 6 replicate exposures per dose, *p < 0.05. e c-Jun transcriptional targets upregualted in endothelial cells treated 4-h in vitro with serum collected 4-h after MWCNT or DM control exposures. Mean log2 fold change results plotted, n = 4 replicate mouse exposures per dose, p < 0.01