The Role of Autophagy as a Mechanism of Toxicity Induced by Multi-Walled Carbon Nanotubes in Human Lung Cells

Tsukahara, Tamotsu; Matsuda, Yoshikaszu; Haniu, Hisao

doi:10.3390/ijms16010040

Cited by 23 publications

(16 citation statements)

References 50 publications

(73 reference statements)

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“…The role of myofibroblasts was discussed in Dong et al [ 72 ]. The other proposed mechanisms include activation of inflammasome [ 73 ], accumulation of CNTs in autophagosomes and disruption of autophagy process [ 74 ], activation of TGFb/smad signaling [ 75 ], and activation of epithelial-mesenchymal transition. However, essentiality of these key events or molecules in the disease process of lung fibrosis induced by carbon nanotubes is yet to be established.…”

Section: Discussionmentioning

confidence: 99%

Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework

et al. 2017

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BackgroundThe accumulation of MWCNTs in the lung environment leads to inflammation and the development of disease similar to pulmonary fibrosis in rodents. Adverse Outcome Pathways (AOPs) are a framework for defining and organizing the key events that comprise the biological changes leading to undesirable events. A putative AOP has been developed describing MWCNT-induced pulmonary fibrosis; inflammation and the subsequent healing response induced by inflammatory mechanisms have been implicated in disease progression.The objective of the present study was to address a key data gap in this AOP: empirical data supporting the essentiality of pulmonary inflammation as a key event prior to fibrosis. Specifically, Interleukin-1 Receptor1 (IL-1R1) and Signal Transducer and Activator of Transcription 6 (STAT6) knock-out (KO) mice were employed to target inflammation and the subsequent healing response using MWCNTs as a model pro-fibrotic stressor to determine whether this altered the development of fibrosis.ResultsWild type (WT) C57BL/6, IL-1R1 (KO) or STAT6 KO mice were exposed to a high dose of Mitsui-7 MWCNT by intratracheal administration. Inflammation was assessed 24 h and 28 days post MWCNT administration, and fibrotic lesion development was assessed 28 days post MWCNT administration. MWCNT-induced acute inflammation was suppressed in IL-1R1 KO mice at the 24 h time point relative to WT mice, but this suppression was not observed 28 days post exposure, and IL-1R1 KO did not alter fibrotic disease development. In contrast, STAT6 KO mice exhibited suppressed acute inflammation and attenuated fibrotic disease in response to MWCNT administration compared to STAT6 WT mice. Whole genome analysis of all post-exposure time points identified a subset of differentially expressed genes associated with fibrosis in both KO mice compared to WT mice.ConclusionThe findings support the essentiality of STAT6-mediated signaling in the development of MWCNT-induced fibrotic disease. The IL-1R1 KO results also highlight the nature of the inflammatory response associated with MWCNT exposure, and indicate a system with multiple redundancies. These data add to the evidence supporting an existing AOP, and will be useful in designing screening strategies that could be used by regulatory agencies to distinguish between MWCNTs of varying toxicity.Electronic supplementary materialThe online version of this article (10.1186/s12989-017-0218-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework

et al. 2017

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“…Apoptosis and inflammatory response have been shown in macrophages treated with graphene quantum dots [21]. On the other hand, GO nanoparticles at low dosages have been shown not to induce apoptosis [22,23]. …”

Section: Discussionmentioning

confidence: 99%

Graphene Oxide Nanoribbons Induce Autophagic Vacuoles in Neuroblastoma Cell Lines

Mari

Mardente

Morgante

et al. 2016

IJMS

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Since graphene nanoparticles are attracting increasing interest in relation to medical applications, it is important to understand their potential effects on humans. In the present study, we prepared graphene oxide (GO) nanoribbons by oxidative unzipping of single-wall carbon nanotubes (SWCNTs) and analyzed their toxicity in two human neuroblastoma cell lines. Neuroblastoma is the most common solid neoplasia in children. The hallmark of these tumors is the high number of different clinical variables, ranging from highly metastatic, rapid progression and resistance to therapy to spontaneous regression or change into benign ganglioneuromas. Patients with neuroblastoma are grouped into different risk groups that are characterized by different prognosis and different clinical behavior. Relapse and mortality in high risk patients is very high in spite of new advances in chemotherapy. Cell lines, obtained from neuroblastomas have different genotypic and phenotypic features. The cell lines SK-N-BE(2) and SH-SY5Y have different genetic mutations and tumorigenicity. Cells were exposed to low doses of GO for different times in order to investigate whether GO was a good vehicle for biological molecules delivering individualized therapy. Cytotoxicity in both cell lines was studied by measuring cellular oxidative stress (ROS), mitochondria membrane potential, expression of lysosomial proteins and cell growth. GO uptake and cytoplasmic distribution of particles were studied by Transmission Electron Microscopy (TEM) for up to 72 h. The results show that GO at low concentrations increased ROS production and induced autophagy in both neuroblastoma cell lines within a few hours of exposure, events that, however, are not followed by growth arrest or death. For this reason, we suggest that the GO nanoparticle can be used for therapeutic delivery to the brain tissue with minimal effects on healthy cells.

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“…Although it has been reported that autophagy signaling pathways can be used as an entry point for the treatment of many diseases, which is valuable in both theory and clinical applications, the relationship between autophagy and related signaling pathways is still not clear (Hsieh et al, 2016;Kre Rtowski et al, 2016;Poillet-Perez et al, 2015;Tsukahara et al, 2015). This study investigated the possible mechanism in the differentiation of osteoblasts through a preliminary study on NF-jB signaling pathways and autophagy.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of NF-κB signaling pathway and autophagy in the regulation of osteoblast differentiation

Han

Gong

2016

Molecular Membrane Biology

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The Role of Autophagy as a Mechanism of Toxicity Induced by Multi-Walled Carbon Nanotubes in Human Lung Cells

Cited by 23 publications

References 50 publications

Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework

Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework

Graphene Oxide Nanoribbons Induce Autophagic Vacuoles in Neuroblastoma Cell Lines

Mechanism of NF-κB signaling pathway and autophagy in the regulation of osteoblast differentiation

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