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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Part+Fibre+Toxicol
2016 ; 13
(1
): 27
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Multi-walled carbon nanotubes directly induce epithelial-mesenchymal transition
in human bronchial epithelial cells via the TGF-?-mediated Akt/GSK-3?/SNAIL-1
signalling pathway
#MMPMID27251132
Polimeni M
; Gulino GR
; Gazzano E
; Kopecka J
; Marucco A
; Fenoglio I
; Cesano F
; Campagnolo L
; Magrini A
; Pietroiusti A
; Ghigo D
; Aldieri E
Part Fibre Toxicol
2016[Jun]; 13
(1
): 27
PMID27251132
show ga
BACKGROUND: Multi-walled carbon nanotubes (MWCNT) are currently under intense
toxicological investigation due to concern on their potential health effects.
Current in vitro and in vivo data indicate that MWCNT exposure is strongly
associated with lung toxicity (inflammation, fibrosis, granuloma, cancer and
airway injury) and their effects might be comparable to asbestos-induced
carcinogenesis. Although fibrosis is a multi-origin disease,
epithelial-mesenchymal transition (EMT) is recently recognized as an important
pathway in cell transformation. It is known that MWCNT exposure induces EMT
through the activation of the TGF-?/Smad signalling pathway thus promoting
pulmonary fibrosis, but the molecular mechanisms involved are not fully
understood. In the present work we propose a new mechanism involving a
TGF-?-mediated signalling pathway. METHODS: Human bronchial epithelial cells were
incubated with two different MWCNT samples at various concentrations for up to
96 h and several markers of EMT were investigated. Quantitative real time PCR,
western blot, immunofluorescent staining and gelatin zymographies were performed
to detect the marker protein alterations. ELISA was performed to evaluate TGF-?
production. Experiments with neutralizing anti-TGF-? antibody, specific
inhibitors of GSK-3? and Akt and siRNA were carried out in order to confirm their
involvement in MWCNT-induced EMT. In vivo experiments of pharyngeal aspiration in
C57BL/6 mice were also performed. Data were analyzed by a one-way ANOVA with
Tukey's post-hoc test. RESULTS: Fully characterized MWCNT (mean length?5 ?m)
are able to induce EMT in an in vitro human model (BEAS-2B cells) after long-term
incubation at sub-cytotoxic concentrations. MWCNT stimulate TGF-? secretion, Akt
activation and GSK-3? inhibition, which induces nuclear accumulation of SNAIL-1
and its transcriptional activity, thus contributing to switch on the EMT program.
Moreover, a significant increment of nuclear ?-catenin - due to E-cadherin
repression and following translocation to nucleus - likely reinforces signalling
for EMT promotion. In vivo results supported the occurrence of pulmonary fibrosis
following MWCNT exposure. CONCLUSIONS: We demonstrate a new molecular mechanism
of MWCNT-mediated EMT, which is Smad-independent and involves TGF-? and its
intracellular effectors Akt/GSK-3? that activate the SNAIL-1 signalling pathway.
This finding suggests potential novel targets in the development of therapeutic
and preventive approaches.