title: Pulmonary instillation of MWCNT increases lung permeability, decreases gp130 expression in the lungs, and initiates cardiovascular IL-6 transsignaling.
abstract: Pulmonary instillation of multiwalled carbon nanotubes (MWCNT) has the potential to promote cardiovascular derangements, but the mechanisms responsible are currently unclear. We hypothesized that exposure to MWCNT would result in increased epithelial barrier permeability by 24 h postexposure and initiate a signaling process involving IL-6/gp130 transsignaling in peripheral vascular tissue. To test this hypothesis we assessed the impact of 1 and 10 μg/cm(2) MWCNT on transepithelial electrical resistance (TEER) and expression of barrier proteins and cell activation in vitro using normal human bronchial epithelial primary cells. Parallel studies using male Sprague-Dawley rats instilled with 100 μg MWCNT measured bronchoalveolar lavage (BAL) differential cell counts, BAL fluid total protein, and lung water-to-tissue weight ratios 24 h postexposure and quantified serum concentrations of IL-6, soluble IL-6r, and soluble gp130. Aortic sections were examined immunohistochemically for gp130 expression, and gp130 mRNA/protein expression was evaluated in rat lung, heart, and aortic tissue homogenates. Our in vitro findings indicate that 10 μg/cm(2) MWCNT decreased the development of TEER and zonula occludens-1 expression relative to the vehicle. In rats MWCNT instillation increased BAL protein, lung water, and induced pulmonary eosinophilia. Serum concentrations of soluble gp130 decreased, aortic endothelial expression of gp130 increased, and expression of gp130 in the lung was downregulated in the MWCNT-exposed group. We propose that pulmonary exposure to MWCNT can manifest as a reduced epithelial barrier and activator of vascular gp130-associated transsignaling that may promote susceptibility to cardiovascular derangements.
authors.affiliation: Department of Physiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina;
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Thompson
authors.affiliation: Department of Physiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina;
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Holland
authors.affiliation: NanoHealth Program, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina; and.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Snyder
authors.affiliation: Department of Pharmacology & Toxicology, Brody School of Medicine at East Carolina University, Greenville, North Carolina;
authors.forename: Bin
authors.initials: B
authors.lastname: Luo
authors.affiliation: Department of Physiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina;
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Becak
authors.affiliation: Department of Physiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina;
authors.forename: Jillian T
authors.initials: JT
authors.lastname: Odom
authors.affiliation: Wake Forest University Institute of Regenerative Medicine, Winston-Salem, North Carolina.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Harrison
authors.affiliation: Department of Pharmacology & Toxicology, Brody School of Medicine at East Carolina University, Greenville, North Carolina;
authors.forename: Jared M
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Department of Pharmacology & Toxicology, Brody School of Medicine at East Carolina University, Greenville, North Carolina;
authors.forename: Kymberly M
authors.initials: KM
authors.lastname: Gowdy
authors.affiliation: Department of Physiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina; wingardc@ecu.edu.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wingard
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism*; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D037742:Nanotubes, Carbon; D010539:Permeability; D011651:Pulmonary Artery / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D015850:Interleukin-6; D037742:Nanotubes, Carbon; D050822:Cytokine Receptor gp130
keywords: blood vessels; carbon nanotubes; endothelium; soluble IL-6 receptor