title: Long-term intravenous administration of carboxylated single-walled carbon nanotubes induces persistent accumulation in the lungs and pulmonary fibrosis via the nuclear factor-kappa B pathway.
abstract: Numerous studies have demonstrated promising application of single-walled carbon nanotubes (SWNTs) in drug delivery, diagnosis, and targeted therapy. However, the adverse health effects resulting from intravenous injection of SWNTs are not completely understood. Studies have shown that levels of "pristine" or carboxylated carbon nanotubes are very high in mouse lungs after intravenous injection. We hypothesized that long-term and repeated intravenous administration of carboxylated SWNTs (c-SWNTs) can result in persistent accumulation and induce histopathologic changes in rat lungs. Here, c-SWNTs were administered repeatedly to rats via tail-vein injection for 90 days. Long-term intravenous injection of c-SWNTs caused sustained embolization in lung capillaries and granuloma formation. It also induced a persistent inflammatory response that was regulated by the nuclear factor-kappa B signaling pathway, and which resulted in pulmonary fibrogenesis. c-SWNTs trapped within lung capillaries traversed capillary walls and injured alveolar epithelial cells, thereby stimulating production of pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta) and pro-fibrotic growth factors (transforming growth factor-beta 1). Protein levels of type-I and type-III collagens, matrix metalloproteinase-2, and the tissue inhibitor of metalloproteinase-2 were upregulated after intravenous exposure to c-SWNTs as determined by immunohistochemical assays and Western blotting, which suggested collagen deposition and remodeling of the extracellular matrix. These data suggest that chronic and cumulative toxicity of nanomaterials to organs with abundant capillaries should be assessed if such nanomaterials are applied via intravenous administration.
authors.affiliation: Pharmaceutical College, Guangxi Medical University.
authors.forename: Yue
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Pharmacy, The Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region.
authors.forename: Suning
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pharmacy, The Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region.
authors.forename: Gan
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Pharmaceutical College, Guangxi Medical University.
authors.forename: Xuanhao
authors.initials: X
authors.lastname: Fu
authors.affiliation: Pharmaceutical College, Guangxi Medical University.
authors.forename: Xueping
authors.initials: X
authors.lastname: Xie
authors.affiliation: Pharmaceutical College, Guangxi Medical University.
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi, People's Republic of China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Pharmaceutical College, Guangxi Medical University.
authors.forename: Jinbin
authors.initials: J
authors.lastname: Wei
authors.affiliation: Pharmaceutical College, Guangxi Medical University.
authors.forename: Huagang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Pharmaceutical College, Guangxi Medical University.
authors.forename: Zefeng
authors.initials: Z
authors.lastname: Lai
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D002196:Capillaries / Q000187:drug effects; D002264:Carboxylic Acids / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007275:Injections, Intravenous; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D037742:Nanotubes, Carbon / Q000737:chemistry / Q000633:toxicity*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002264:Carboxylic Acids; D016207:Cytokines; D016328:NF-kappa B; D037742:Nanotubes, Carbon
keywords: NF-κB; capillary embolization; carbon nanotubes; inflammation; lung fibrosis