Journal
CHEMICAL RESEARCH IN TOXICOLOGY
Volume 24, Issue 12, Pages 2237-2248Publisher
AMER CHEMICAL SOC
DOI: 10.1021/tx200351d
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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 mu g/mL, <= 24 h). MWCNTs induced substantial ROS production and mitochondrial damage, implicating oxidative stress in cellular damage by MWCNT. MWCNTs activated the NF-kappa B signaling pathway in macrophages (RAW264.7) to increase the secretion of a panel of cytokines and chemokines (TNF alpha, IL-1 beta, IL-6, IL-10, and MCP1) that promote inflammation. Activation of NF-kappa B involved rapid degradation of I kappa B alpha, nuclear accumulation of NF-kappa Bp65, binding of NF-kappa B to specific DNA-binding sequences, and transactivation of target gene promoters. Finally, MWCNTs induced the production of profibrogenic growth factors TGF beta 1 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.
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