Multiwall Carbon Nanotubes Mediate Macrophage Activation and Promote Pulmonary Fibrosis Through TGF‐β/Smad Signaling Pathway

Abstract

Multiwall carbon nanotubes (MWCNTs) have been widely used in many disciplines due to their unique physical and chemical properties, but have also raised great concerns about their possible negative health impacts, especially through occupational exposure. Although recent studies have demonstrated that MWCNTs induce granuloma formation and/or fibrotic responses in the lungs of rats or mice, their cellular and molecular mechanisms remain largely unaddressed. Here, it is reported that the TGF-β/Smad signaling pathway can be activated by MWCNTs and play a critical role in MWCNT-induced pulmonary fibrosis. Firstly, in vivo data show that spontaneously hypertensive (SH) rats administered long MWCNTs (20-50 μm) but not short MWCNTs (0.5-2 μm) exhibit increased fibroblast proliferation, collagen deposition and granuloma formation in lung tissue. Secondly, the in vivo experiments also indicate that only long MWCNTs can significantly activate macrophages and increase the production of transforming growth factor (TGF)-β1, which induces the phosphorylation of Smad2 and then the expression of collagen I/III and extracellular matrix (ECM) protease inhibitors in lung tissues. Finally, the present in vitro studies further demonstrate that the TGF-β/Smad signaling pathway is indeed necessary for the expression of collagen III in fibroblast cells. Together, these data demonstrate that MWCNTs stimulate pulmonary fibrotic responses such as fibroblast proliferation and collagen deposition in a TGF-β/Smad-dependent manner. These observations also suggest that tube length acts as an important factor in MWCNT-induced macrophage activation and subsequent TGF-β1 secretion. These in vivo and in vitro studies further highlight the potential adverse health effects that may occur following MWCNT exposure and provide a better understanding of the cellular and molecular mechanisms by which MWCNTs induce pulmonary fibrotic reactions.

Systematic in vitro nanotoxicity study on anodic alumina nanotubes with engineered aspect ratio: Understanding nanotoxicity by a nanomaterial model

“…Biopersistent nanofibers with stiff nanostructures can induce significant inflammation, fibrosis or granuloma when these nanostructures are too long to be phagocytized by macrophages. Carbon nanotubes (CNTs) as the most well-known HAR nanomaterial can trigger pulmonary toxicity due to fibrosis, which is mainly caused by macrophage activation, TGF-b induction and enhanced collagen deposition [6,7].…”

Bacterial endotoxin (lipopolysaccharide) binds to the surface of gold nanoparticles, interferes with biocorona formation and induces human monocyte inflammatory activation

“…Nanosafety studies depend on scientific reports on the biological effects of nanoparticles (NPs) in living organisms, in order to predict and correct the possible deleterious impact on human and environmental health. Many studies showed that NPs may have adverse effects on health, mainly due to their small size, large surface area per mass and highly reactive properties (Bast us et al 2008;Ge et al 2012;Li et al 2012;Wang et al 2013). Among the different NP effects in biological systems, activation of immune responses is considered a central element for assessing health risks of NPs (Boraschi and Duschl 2012;).…”

<div>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</div>

“…16 The transforming growth factor-beta (TGF-β) signaling cascade has been elaborated to be involved in CNTinduced pulmonary inflammation, epithelial-to-mesenchymal transition (EMT), and fibrogenesis. [17][18][19][20][21] Biomedical applications such as delivery of therapeutic agents and imaging diagnosis based on CNTs are carried out mainly via intravenous or subcutaneous routes. Hence, the biocompatibility and safety of CNTs introduced directly into the bloodstream or other biologic tissue should be assessed.…”

“…18 Subsequently, the phosphorylated Smad2 heterodimerizes with Smad4 to form Smad2/4 complexes that translocate to the nucleus and bind to the promoter regions of pro-fibrotic genes such as collagen and α-SMA.…”