Pulmonary delivery of the broad-spectrum matrix metalloproteinase inhibitor marimastat diminishes multiwalled carbon nanotube-induced circulating bioactivity without reducing pulmonary inflammation

Abstract

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-1β, IL-6, and TNF-α), 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.

Characterization of Mild Delayed Gestational Hypertension in Rats Following Ozone Exposure

“…As an important component of the mechanisms by which inhaled pollutants impact the systemic vasculature, we have identi ed that fragmented peptides arising from pulmonary peptidase activity in response to pollutants [31] can directly stimulate endothelial in ammatory responses in coronary, mesenteric, and cerebrovascular beds [32][33][34], and there is little reason to assume that the placental vascular bed is not similarly vulnerable to the systemic effects of inhaled toxicants. As a speci c example, a fragmented thrombospondin-1 peptide (corresponding to amino acids 402-460) was highly upregulated in serum after pulmonary particulate matter exposure and was observed to reduce endothelial cell growth rates, most likely via interaction with the CD36 receptor.…”

Nanotechnology’s frontier in combatting infectious and inflammatory diseases: prevention and treatment

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