Multiwalled carbon nanotubes damage the mitochondria to increase reactive oxygen radical production, activate NF-kB signaling to induce inflammatory cytokines, & stimulate transforming growth factor ß1 & platelet-derived growth factor expression to promote fibroblast-to-myofibroblast transformation
He-X; Young-S; Schwegler-Berry-D; Chishom-WP; Fernback-JE; Ma-Q
Toxicologist 2013 Mar; 132(1):95
Carbon nanotubes (CNTs) are novel material with unique electronic and mechanical properties. Here, we report that multi-walled carbon nanotubes (MWCNT) have potent, dose-dependent toxicity on cultured human cells. Molecular characterization revealed that MWCNT induced substantial ROS production and mitochondrial inner membrane depolarization at sub-toxic doses. MWCNT stimulated the secretion of a panel of inflammatory cytokines and chemokines (TNFalpha, IL-1beta, IL-6, IL-10 and MCP1) from macrophages (Raw264.7) by activating the canonical NF-kappaB signaling pathway. Activation of NF-kappaB signaling involves rapid degradation of IkapaBalpha, nuclear accumulation of NF-kappaBp65, binding of NF-kappaB to specific DNA-binding sequences, and transactivation of target gene promoters. Finally, MWCNTs induced the production of fibrogenic growth factors TGFbeta1 and PDGF that function as paracrine signals to promote the transformation of lung fibroblasts into myofibroblasts, a key molecular step in the development of lung fibrosis. These results demonstrated that MWCNT elicit multiple and intertwining molecular signaling events involving oxidative damage, inflammatory cytokine production, and myofibroblast transformation, which potentially underlie the toxicity and fibrosis in human lungs by MWCNTs.
Toxicology; Nanotechnology; Carcinogenicity; Dose-response; Cytotoxic-effects; Oxidative-processes; Cell-alteration; Cell-damage; Cell-transformation; Cellular-reactions; Genes; DNA-damage; Gene-mutation; Growth-factors; Lung-cells; Connective-tissue; Muscle-cells; Lung-fibrosis; Cell-cultures; Molecular-biology; Immune-reaction
The Toxicologist. Society of Toxicology 52nd Annual Meeting and ToxExpo, March 10-14, 2013, San Antonio, Texas