title: Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood-brain barrier impairment.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Mario J
authors.initials: MJ
authors.lastname: Aragon
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Lauren
authors.initials: L
authors.lastname: Topper
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Tyler
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Bethany
authors.initials: B
authors.lastname: Sanchez
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Katherine
authors.initials: K
authors.lastname: Zychowski
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Tamara
authors.initials: T
authors.lastname: Young
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Guy
authors.initials: G
authors.lastname: Herbert
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Pamela
authors.initials: P
authors.lastname: Hall
authors.affiliation: Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, WV 26505.
authors.forename: Aaron
authors.initials: A
authors.lastname: Erdely
authors.affiliation: Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, WV 26505.
authors.forename: Tracy
authors.initials: T
authors.lastname: Eye
authors.affiliation: Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, WV 26505.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Bishop
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Saunders
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Pretal P
authors.initials: PP
authors.lastname: Muldoon
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298 akottens@vcu.edu mcampen@salud.unm.edu.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Ottens
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131; akottens@vcu.edu mcampen@salud.unm.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Campen
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D004337:Drug Carriers / Q000009:adverse effects*; D004660:Encephalitis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019793:Fluorescein / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D037742:Nanotubes, Carbon / Q000009:adverse effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000235:genetics
chemical_list: D018955:CD36 Antigens; D004337:Drug Carriers; D005456:Fluorescent Dyes; D037742:Nanotubes, Carbon; D047428:Protein Kinase Inhibitors; D019700:Thrombospondin 1; C000611726:thrombospondin-1, human; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil; D019793:Fluorescein
keywords: blood-brain barrier; microglia; multiwalled carbon nanotube; nanoparticle; thrombospondin-1