title: Multiwalled carbon nanotubes induce a fibrogenic response by stimulating reactive oxygen species production, activating NF-κB signaling, and promoting fibroblast-to-myofibroblast transformation.
abstract: Carbon nanotubes (CNTs) are novel materials with unique electronic and mechanical properties. The extremely small size, fiberlike shape, large surface area, and unique surface chemistry render their distinctive chemical and physical characteristics and raise potential hazards to humans. Several reports have shown that pulmonary exposure to CNTs caused inflammation and lung fibrosis in rodents. The molecular mechanisms that govern CNT lung toxicity remain largely unaddressed. Here, we report that multiwalled carbon nanotubes (MWCNTs) have potent, dose-dependent toxicity on cultured human lung cells (BEAS-2B, A549, and WI38-VA13). Mechanistic analyses were carried out at subtoxic doses (≤20 μg/mL, ≤ 24 h). MWCNTs induced substantial ROS production and mitochondrial damage, implicating oxidative stress in cellular damage by MWCNT. MWCNTs activated the NF-κB signaling pathway in macrophages (RAW264.7) to increase the secretion of a panel of cytokines and chemokines (TNFα, IL-1β, IL-6, IL-10, and MCP1) that promote inflammation. Activation of NF-κB involved rapid degradation of IκBα, nuclear accumulation of NF-κBp65, binding of NF-κB to specific DNA-binding sequences, and transactivation of target gene promoters. Finally, MWCNTs induced the production of profibrogenic growth factors TGFβ1 and PDGF from macrophages that function as paracrine signals to promote the transformation of lung fibroblasts (WI38-VA13) into myofibroblasts, a key step in the development of fibrosis. Our results revealed that MWCNTs elicit multiple and intertwining signaling events involving oxidative damage, inflammatory cytokine production, and myofibroblast transformation, which potentially underlie the toxicity and fibrosis in human lungs by MWCNTs.
authors.affiliation: Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia 26505, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: He
authors.forename: Shih-Houng
authors.initials: SH
authors.lastname: Young
authors.forename: Diane
authors.initials: D
authors.lastname: Schwegler-Berry
authors.forename: William P
authors.initials: WP
authors.lastname: Chisholm
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Fernback
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ma
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D005355:Fibrosis / Q000503:physiopathology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D058628:Myofibroblasts / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism*; D037742:Nanotubes, Carbon / Q000633:toxicity*; D018384:Oxidative Stress; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D016328:NF-kappa B; D037742:Nanotubes, Carbon; D010982:Platelet-Derived Growth Factor; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1