title: Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice.
abstract: Single-walled carbon nanotubes (SWCNT) are new materials of emerging technological importance. As SWCNT are introduced into the life cycle of commercial products, their effects on human health and environment should be addressed. We demonstrated that pharyngeal aspiration of SWCNT elicited unusual pulmonary effects in C57BL/6 mice that combined a robust but acute inflammation with early onset yet progressive fibrosis and granulomas. A dose-dependent increase in the protein, LDH, and gamma-glutamyl transferase activities in bronchoalveolar lavage were found along with accumulation of 4-hydroxynonenal (oxidative biomarker) and depletion of glutathione in lungs. An early neutrophils accumulation (day 1), followed by lymphocyte (day 3) and macrophage (day 7) influx, was accompanied by early elevation of proinflammatory cytokines (TNF-alpha, IL-1beta; day 1) followed by fibrogenic transforming growth factor (TGF)-beta1 (peaked on day 7). A rapid progressive fibrosis found in mice exhibited two distinct morphologies: 1) SWCNT-induced granulomas mainly associated with hypertrophied epithelial cells surrounding SWCNT aggregates and 2) diffuse interstitial fibrosis and alveolar wall thickening likely associated with dispersed SWCNT. In vitro exposure of murine RAW 264.7 macrophages to SWCNT triggered TGF-beta1 production similarly to zymosan but generated less TNF-alpha and IL-1beta. SWCNT did not cause superoxide or NO.production, active SWCNT engulfment, or apoptosis in RAW 264.7 macrophages. Functional respiratory deficiencies and decreased bacterial clearance (Listeria monocytogenes) were found in mice treated with SWCNT. Equal doses of ultrafine carbon black particles or fine crystalline silica (SiO2) did not induce granulomas or alveolar wall thickening and caused a significantly weaker pulmonary inflammation and damage.
authors.affiliation: Health Effects Laboratory Div., NIOSH, Morgantown, WV, USA. AShvedova@cdc.gov
authors.forename: Anna A
authors.initials: AA
authors.lastname: Shvedova
authors.forename: Elena R
authors.initials: ER
authors.lastname: Kisin
authors.forename: Robert
authors.initials: R
authors.lastname: Mercer
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Murray
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Johnson
authors.forename: Alla I
authors.initials: AI
authors.lastname: Potapovich
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Tyurina
authors.forename: Olga
authors.initials: O
authors.lastname: Gorelik
authors.forename: Sevaram
authors.initials: S
authors.lastname: Arepalli
authors.forename: Diane
authors.initials: D
authors.lastname: Schwegler-Berry
authors.forename: Ann F
authors.initials: AF
authors.lastname: Hubbs
authors.forename: James
authors.initials: J
authors.lastname: Antonini
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Evans
authors.forename: Bon-Ki
authors.initials: BK
authors.lastname: Ku
authors.forename: Dawn
authors.initials: D
authors.lastname: Ramsey
authors.forename: Andrew
authors.initials: A
authors.lastname: Maynard
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.forename: Vincent
authors.initials: V
authors.lastname: Castranova
authors.forename: Paul
authors.initials: P
authors.lastname: Baron
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005978:Glutathione / Q000378:metabolism; D015745:Granuloma, Foreign-Body / Q000209:etiology / Q000473:pathology; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000473:pathology*; D008171:Lung Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D037742:Nanotubes, Carbon / Q000737:chemistry / Q000633:toxicity*; D011014:Pneumonia / Q000209:etiology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000473:pathology; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D037742:Nanotubes, Carbon; D007770:L-Lactate Dehydrogenase; D005723:gamma-Glutamyltransferase; D005978:Glutathione