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Title: Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood-brain barrier impairment.

Authors: Aragon, Mario J; Topper, Lauren; Tyler, Christina R; Sanchez, Bethany; Zychowski, Katherine; Young, Tamara; Herbert, Guy; Hall, Pamela; Erdely, Aaron; Eye, Tracy; Bishop, Lindsey; Saunders, Samantha A; Muldoon, Pretal P; Ottens, Andrew K; Campen, Matthew J

Published In Proc Natl Acad Sci U S A, (2017 Mar 07)

Abstract: Pulmonary exposure to multiwalled carbon nanotubes (MWCNTs) causes indirect systemic inflammation through unknown pathways. MWCNTs translocate only minimally from the lungs into the systemic circulation, suggesting that extrapulmonary toxicity may be caused indirectly by lung-derived factors entering the circulation. To assess a role for MWCNT-induced circulating factors in driving neuroinflammatory outcomes, mice were acutely exposed to MWCNTs (10 or 40 µg/mouse) via oropharyngeal aspiration. At 4 h after MWCNT exposure, broad disruption of the blood-brain barrier (BBB) was observed across the capillary bed with the small molecule fluorescein, concomitant with reactive astrocytosis. However, pronounced BBB permeation was noted, with frank albumin leakage around larger vessels (>10 µm), overlain by a dose-dependent astroglial scar-like formation and recruitment of phagocytic microglia. As affirmed by elevated inflammatory marker transcription, MWCNT-induced BBB disruption and neuroinflammation were abrogated by pretreatment with the rho kinase inhibitor fasudil. Serum from MWCNT-exposed mice induced expression of adhesion molecules in primary murine cerebrovascular endothelial cells and, in a wound-healing in vitro assay, impaired cell motility and cytokinesis. Serum thrombospondin-1 level was significantly increased after MWCNT exposure, and mice lacking the endogenous receptor CD36 were protected from the neuroinflammatory and BBB permeability effects of MWCNTs. In conclusion, acute pulmonary exposure to MWCNTs causes neuroinflammatory responses that are dependent on the disruption of BBB integrity.

PubMed ID: 28223486 Exiting the NIEHS site

MeSH Terms: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives*; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology; Administration, Inhalation; Animals; Astrocytes/drug effects; Astrocytes/metabolism; Astrocytes/pathology; Blood-Brain Barrier/drug effects*; Blood-Brain Barrier/metabolism; Blood-Brain Barrier/pathology; Brain/drug effects; Brain/metabolism; Brain/pathology; CD36 Antigens/deficiency; CD36 Antigens/genetics; Cell Movement/drug effects; Drug Carriers/adverse effects*; Encephalitis/chemically induced; Encephalitis/genetics; Encephalitis/pathology; Encephalitis/prevention & control*; Endothelial Cells/drug effects; Endothelial Cells/metabolism; Endothelial Cells/pathology; Fluorescein/pharmacokinetics; Fluorescent Dyes/pharmacokinetics; Lung/drug effects; Lung/metabolism; Lung/pathology; Mice; Nanotubes, Carbon/adverse effects*; Protein Kinase Inhibitors/pharmacology*; Thrombospondin 1/genetics; Thrombospondin 1/metabolism; rho-Associated Kinases/genetics

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