Multiwall Carbon Nanotubes Directly Promote Fibroblast–Myofibroblast and Epithelial–Mesenchymal Transitions through the Activation of the TGF‐β/Smad Signaling Pathway

A number of studies have demonstrated that MWCNTs induce granuloma formation and fibrotic responses in vivo, and it has been recently reported that MWCNT‐induced macrophage activation and subsequent TGF‐β secretion contribute to pulmonary fibrotic responses. However, their direct effects against alveolar type‐II epithelial cells and fibroblasts and the corresponding underlying mechanisms remain largely unaddressed. Here, MWCNTs are reported to be able to directly promote fibroblast‐to‐myofibroblast conversion and the epithelial–mesenchymal transition (EMT) through the activation of the TGF‐β/Smad signaling pathway. Both of the cell transitions may play important roles in MWCNT‐induced pulmonary fibrosis. Firstly, in‐vivo and in‐vitro data show that long MWCNTs can directly interact with fibroblasts and epithelial cells, and some of them may be uptaken into fibroblasts and epithelial cells by endocytosis. Secondly, long MWCNTs can directly activate fibroblasts and increase both the basal and TGF‐β1‐induced expression of the fibroblast‐specific protein‐1, α‐smooth muscle actin, and collagen III. Finally, MWCNTs can induce the EMT through the activation of TGF‐β/Smad2 signaling in alveolar type‐II epithelial cells, from which some fibroblasts involved in pulmonary fibrosis are thought to originate. These observations suggest that the activation of the TGF‐β/Smad2 signaling plays a critical role in the process of the fibroblast‐to‐myofibroblast transition and the EMT induced by MWCNTs.