Reactive oxygen species-mediated p38 MAPK regulates carbon nanotube-induced fibrogenic and angiogenic responses

Department of Pharmaceutical Sciences, Hampton University , Hampton, VA , USA.
Nanotoxicology (Impact Factor: 6.41). 01/2012; 7(2). DOI: 10.3109/17435390.2011.647929
Source: PubMed


Abstract Single-walled carbon nanotubes (SWCNTs) are fibrous nanoparticles that are being used widely for various applications including drug delivery. SWCNTs are currently under special attention for possible cytotoxicity. Recent reports suggest that exposure to nanoparticles leads to pulmonary fibrosis. We report that SWCNT-mediated interplay of fibrogenic and angiogenic regulators leads to increased angiogenesis, which is a novel finding that furthers the understanding of SWCNT-induced cytotoxicity. SWCNTs induce fibrogenesis through reactive oxygen species-regulated phosphorylation of p38 mitogen-activated protein kinase (MAPK). Activation of p38 MAPK by SWCNTs led to the induction of transforming growth factor (TGF)-β1 as well as vascular endothelial growth factor (VEGF). Both TGF-β1 and VEGF contributed significantly to the fibroproliferative and collagen-inducing effects of SWCNTs. Interestingly, a positive feedback loop was observed between TGF-β1 and VEGF. This interplay of fibrogenic and angiogenic mediators led to increased angiogenesis in response to SWCNTs. Overall this study reveals key signalling molecules involved in SWCNT-induced fibrogenesis and angiogenesis.

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    • "Gill irritation and apoptotic bodies in liver cells are found in the SWCNT-exposed rainbow trout Oncorhynchus mykiss (Smith et al., 2007). Some studies in normal and malignant human mesothelial cells and the human lung fibroblast cell line CRL-1490 showed that MWCNTs induce ERK and p38 MAP kinase activation followed by inflammation, fibrosis, and apoptosis (Pacurari et al., 2008; Azad et al., 2013; Manke et al., 2013). However, to date, CNT-induced oxidative stress, abnormal MAPK activation, and combined toxicity with copper have not been studied in marine organisms. "
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    ABSTRACT: Multi-walled carbon nanotubes (MWCNTs) are nanoparticles widely applicable in various industrial fields. However, despite the usefulness of MWCNTs in industry, their oxidative stress-induced toxicity, combined toxicity with metal, and mitogen-activated protein kinase (MAPK) activation have not been widely investigated in marine organisms. We used the intertidal copepod Tigriopus japonicus as a test organism to demonstrate the adverse effects induced by MWCNTs in aquatic test organisms. The dispersion of the MWCNTs in seawater was maintained over 48h without aggregation. MWCNTs caused a decrease in acute copper toxicity compared to the copper-only group in response to 20 and 100mg/L MWCNTs, but not in response to 4mg/L MWCNT, indicating that MWCNT may suppress acute copper toxicity. Reactive oxygen species (ROS) and enzymatic activities of glutathione S-transferase (GST) and catalase were significantly down-regulated in response to 100mg/L MWCNT exposure. Glutathione (GSH) and glutathione reductase (GR) activity did not change significantly, indicating that MWCNTs may cause failure of the antioxidant system in T. japonicus. However, MWCNT induced extracellular signal-regulated kinase (ERK) activation without p38 and c-jun NH2-terminal kinase (JNK) activation, suggesting that ERK activation plays a key role in cell signaling pathways downstream of CNT exposure. This suggests that this pathway can be used as a biomarker for CNT exposure in T. japonicus. This study provides a better understanding of the cellular-damage response to MWCNTs.
    Full-text · Article · Dec 2015 · Aquatic Toxicology
    • "To explore the mechanisms responsible for fibroblast proliferation after MWCNT exposure, different hypotheses have been investigated. Some authors have reported increased TGF-bRII protein levels and the secretion of TGF-b by fibroblasts exposed to SWCNT (Azad et al., 2013; Lin et al., 2012; Manke et al., 2014). We did not observe increased PDGF or TGF-b secretion or expression of their receptors by fibroblast exposed to MWCNT. "
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    ABSTRACT: Carbon nanotubes (CNT) have been reported to induce lung inflammation and fibrosis in rodents. We investigated the direct and indirect cellular mechanisms mediating the fibrogenic activity of multi-wall (MW) CNT on fibroblasts. We showed that MWCNT indirectly stimulate lung fibroblast (MLg) differentiation, via epithelial cells and macrophages, whereas no direct effect of MWCNT on fibroblast differentiation or collagen production was detected. MWCNT directly stimulated the proliferation of fibroblasts primed with low concentrations of growth factors, such as PDGF, TGF-β or EGF. MWCNT prolonged ERK 1/2 phosphorylation induced by low concentrations of PDGF or TGF-β in fibroblasts. This phenomenon and the proliferative activity of MWCNT on fibroblasts was abrogated by the inhibitors of ERK 1/2, PDGF-, TGF-β- and EGF-receptors. This activity was also reduced by amiloride, an endocytosis inhibitor. Finally, the lung fibrotic response to several MWCNT samples (different in length and diameter) correlated with their in vitro capacity to stimulate the proliferation of fibroblasts and to prolong ERK 1/2 signaling in these cells. Our findings point to a crosstalk between MWCNT, kinase receptors, ERK 1/2 signaling and endocytosis which stimulates the proliferation of fibroblasts. The mechanisms of action identified in this study contribute to predict the fibrogenic potential of MWCNT.
    No preview · Article · Oct 2015 · Nanotoxicology
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    • "It has been reported that nanomaterials cause these damages [37–39]. It was reported that reactive oxygen species generated by titanium expressed Fas, Bcl-2-associated X protein (Bax), IL-1 beta, and induced apoptosis [40, 41]; those generated by silica induced DNA damage and autophagy [42, 43], those generated by polyvinylpyrrolidone (PVP)-coated silver nanoparticles and silver ions induce apoptosis and necrosis in THP-1 monocytes [44], and those generated by carbon nanotube activated p38 MAPK and NF-κB signaling and induced fibrogenic and angiogenic responses [45–47]. "
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    ABSTRACT: Pulmonary inflammation, especially persistent inflammation, has been found to play a key role in respiratory disorders induced by nanoparticles in animal models. In inhalation studies and instillation studies of nanomaterials, persistent inflammation is composed of neutrophils and alveolar macrophages, and its pathogenesis is related to chemokines such as the cytokine-induced neutrophil chemoattractant (CINC) family and macrophage inflammatory protein-1 α and oxidant stress-related genes such as heme oxygenase-1 (HO-1). DNA damages occur chemically or physically by nanomaterials. Chemical and physical damage are associated with point mutation by free radicals and double strand brake, respectively. The failure of DNA repair and accumulation of mutations might occur when inflammation is prolonged, and finally normal cells could become malignant. These free radicals can not only damage cells but also induce signaling molecules containing immunoreaction. Nanoparticles and asbestos also induce the production of free radicals. In allergic responses, nanoparticles act as Th2 adjuvants to activate Th2 immune responses such as activation of eosinophil and induction of IgE. Taken together, the presence of persistent inflammation may contribute to the pathogenesis of a variety of diseases induced by nanomaterials.
    Full-text · Article · Jul 2014 · Research Journal of Immunology
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