Abstract:Mesothelioma is an incurable form of cancer located most commonly in the pleural lining of the lungs and is associated almost exclusively with the inhalation of asbestos. The binding of asbestos to epidermal growth factor receptor (EGFR), a transmembrane signal protein, has been proposed as a trigger for downstream signaling of kinases and expression of genes involved in cell proliferation and inhibition of apoptosis. Here, we investigate the molecular binding of EGFR to crocidolite (blue asbestos; Na2(Fe(2+),… Show more
“…Currently, no data is available on how CNT could interact with these receptors. Asbestos fibers have been shown to directly bind and activate EGF receptor [ 35 ], suggesting that CNT could somehow interact with kinase receptors. Azad et al [ 14 ] and Vietti et al [ 34 ] have identified different mechanisms leading to CNT-induced fibroblast proliferation.…”
Section: The Direct Effects Of Cnt On Fibroblastsmentioning
confidence: 99%
“…MWCNT (25–100 μg/ml) were shown to induce the release of IL-1β and IL-18 by cultured alveolar macrophages isolated from naive C57BL/6 mice and by human monocytic cell line (THP-1), and their secretion was suppressed by inhibitors of caspase-1 and cathepsin B [ 42 ]. Several other in vitro studies observed that CNT enhanced IL-1β release in macrophages via inflammasome activation, nuclear factor-kappa B (NF-kB) and oxidative stress [ 13 , 35 , 36 , 43 – 47 ], which we discuss in the mechanisms section. Moreover, IL-1β has also been shown to induce the release of the pro-fibrotic mediators TGF-β and PDGF from different cell types, thus highlighting the importance of the pro-inflammatory mediators released by macrophages [ 13 ].…”
Section: Indirect Effects Of Cnt On Fibroblastsmentioning
confidence: 99%
“…Finally, CNT dispersion was also found as another critical factor. Several evidences show that well dispersed CNT stimulate proliferation and collagen production by lung fibroblasts [ 29 , 30 ], induce the release of IL-1β from macrophages [ 13 , 35 , 36 , 43 – 47 ] and TGF-β from epithelial cells [ 36 , 47 ], compared to not dispersed CNT. The extent and localization of CNT and inflammatory cells in the lung was also related to the particle dispersion and agglomeration state before administration.…”
Section: Determinants Of the Fibrotic Activities Of Cntmentioning
Several experimental studies have shown that carbon nanotubes (CNT) can induce respiratory effects, including lung fibrosis. The cellular and molecular events through which these effects develop are, however, not clearly elucidated. The purpose of the present review was to analyze the key events involved in the lung fibrotic reaction induced by CNT and to assess their relationships. We thus address current knowledge and gaps with a view to draft an Adverse Outcome Pathway (AOP) concerning the fibrotic potential of CNT.As for many inhaled particles, CNT can indirectly activate fibroblasts through the release of pro-inflammatory (IL-1β) and pro-fibrotic (PDGF and TGF-β) mediators by inflammatory cells (macrophages and epithelial cells) via the induction of oxidative stress, inflammasome or NF-kB. We also highlight here direct effects of CNT on fibroblasts, which appear as a new mode of toxicity relatively specific for CNT. Direct effects of CNT on fibroblasts include the induction of fibroblast proliferation, differentiation and collagen production via ERK 1/2 or Smad signaling. We also point out the physico-chemical properties of CNT important for their toxicity and the relationship between in vitro and in vivo effects. This knowledge provides evidence to draft an AOP for the fibrogenic activity of CNT, which allows developing simple in vitro models contributing to predict the CNT effects in lung fibrosis, and risk assessment tools for regulatory decision.
“…Currently, no data is available on how CNT could interact with these receptors. Asbestos fibers have been shown to directly bind and activate EGF receptor [ 35 ], suggesting that CNT could somehow interact with kinase receptors. Azad et al [ 14 ] and Vietti et al [ 34 ] have identified different mechanisms leading to CNT-induced fibroblast proliferation.…”
Section: The Direct Effects Of Cnt On Fibroblastsmentioning
confidence: 99%
“…MWCNT (25–100 μg/ml) were shown to induce the release of IL-1β and IL-18 by cultured alveolar macrophages isolated from naive C57BL/6 mice and by human monocytic cell line (THP-1), and their secretion was suppressed by inhibitors of caspase-1 and cathepsin B [ 42 ]. Several other in vitro studies observed that CNT enhanced IL-1β release in macrophages via inflammasome activation, nuclear factor-kappa B (NF-kB) and oxidative stress [ 13 , 35 , 36 , 43 – 47 ], which we discuss in the mechanisms section. Moreover, IL-1β has also been shown to induce the release of the pro-fibrotic mediators TGF-β and PDGF from different cell types, thus highlighting the importance of the pro-inflammatory mediators released by macrophages [ 13 ].…”
Section: Indirect Effects Of Cnt On Fibroblastsmentioning
confidence: 99%
“…Finally, CNT dispersion was also found as another critical factor. Several evidences show that well dispersed CNT stimulate proliferation and collagen production by lung fibroblasts [ 29 , 30 ], induce the release of IL-1β from macrophages [ 13 , 35 , 36 , 43 – 47 ] and TGF-β from epithelial cells [ 36 , 47 ], compared to not dispersed CNT. The extent and localization of CNT and inflammatory cells in the lung was also related to the particle dispersion and agglomeration state before administration.…”
Section: Determinants Of the Fibrotic Activities Of Cntmentioning
Several experimental studies have shown that carbon nanotubes (CNT) can induce respiratory effects, including lung fibrosis. The cellular and molecular events through which these effects develop are, however, not clearly elucidated. The purpose of the present review was to analyze the key events involved in the lung fibrotic reaction induced by CNT and to assess their relationships. We thus address current knowledge and gaps with a view to draft an Adverse Outcome Pathway (AOP) concerning the fibrotic potential of CNT.As for many inhaled particles, CNT can indirectly activate fibroblasts through the release of pro-inflammatory (IL-1β) and pro-fibrotic (PDGF and TGF-β) mediators by inflammatory cells (macrophages and epithelial cells) via the induction of oxidative stress, inflammasome or NF-kB. We also highlight here direct effects of CNT on fibroblasts, which appear as a new mode of toxicity relatively specific for CNT. Direct effects of CNT on fibroblasts include the induction of fibroblast proliferation, differentiation and collagen production via ERK 1/2 or Smad signaling. We also point out the physico-chemical properties of CNT important for their toxicity and the relationship between in vitro and in vivo effects. This knowledge provides evidence to draft an AOP for the fibrogenic activity of CNT, which allows developing simple in vitro models contributing to predict the CNT effects in lung fibrosis, and risk assessment tools for regulatory decision.
“…They may also be associated with oncogenesis (e.g., mesothelioma) through aberrant activation of the cell signaling cascades. A part of this signaling cascade is the activation of EGFR through binding of either biological compounds, such as extracellular ligands (i.e., EGF), or foreign substances . Upon binding to a ligand, the receptor homo‐ or heterodimerizes and autophosphorylation start the signal to the nucleus.…”
The epidermal growth factor receptor (EGFR) is an important transmembrane glycoprotein kinase involved the initiation or perpetuation of signal transduction cascades within cells. These processes occur after EGFR binds to a ligand [epidermal growth factor (EGF)], thus inducing its dimerization and tyrosine autophosphorylation. Previous publications have highlighted the importance of glycosylation and dimerization for promoting proper function of the receptor and conformation in membranes; however, the effects of these associations on the protein conformational stability have not yet been described. Molecular dynamics simulations were performed to characterize the conformational preferences of the monomeric and dimeric forms of the EGFR extracellular domain upon binding to EGF in the presence and absence of N-glycan moieties. Structural stability analyses revealed that EGF provides the most conformational stability to EGFR, followed by glycosylation and dimerization, respectively. The findings also support that EGF–EGFR binding takes place through a large-scale induced-fitting mechanism.
“…NF B role in MWCNT molecular mechanism of toxicity has been extensively studied and is well accepted [96] . Similarly, IL-17 mediates protective innate immunity mechanisms against a plethora of pathogens, and is nowadays regarded a potential pivotal therapeutical target in inflammation pathogenesis [97] , [98] , [99] , [100] , [101] , [102] . Fig.…”
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