Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice.
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.
Shvedova
Anna A
AA
Health Effects Laboratory Div., NIOSH, Morgantown, WV, USA. AShvedova@cdc.gov
Kisin
Elena R
ER
Mercer
Robert
R
Murray
Ashley R
AR
Johnson
Victor J
VJ
Potapovich
Alla I
AI
Tyurina
Yulia Y
YY
Gorelik
Olga
O
Arepalli
Sevaram
S
Schwegler-Berry
Diane
D
Hubbs
Ann F
AF
Antonini
James
J
Evans
Douglas E
DE
Ku
Bon-Ki
BK
Ramsey
Dawn
D
Maynard
Andrew
A
Kagan
Valerian E
VE
Castranova
Vincent
V
Baron
Paul
P
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
D016207:Cytokines; D018836:Inflammation Mediators; D037742:Nanotubes, Carbon; D007770:L-Lactate Dehydrogenase; D005723:gamma-Glutamyltransferase; D005978:Glutathione