Mechanisms of lung fibrosis induced by carbon nanotubes: towards an Adverse Outcome Pathway (AOP)

Vietti, Giulia; Lison, Dominique; Brûle, Sybille van den

doi:10.1186/s12989-016-0123-y

Cited by 125 publications

(117 citation statements)

References 97 publications

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“…The long-term consequences of pulmonary exposure to MWCNT are unclear, but there is increasing evidence supporting a link between MWCNT exposure and development of atherosclerosis. Apolipoprotein E−/− mice fed a western (high fat) diet in conjunction with chronic exposure to MWCNT have been observed exhibiting modest pulmonary inflammation (Han, 2016), oxidative damage to lung DNA, aortic remodeling (Christophersen et al, 2016), accelerated plaque progression (Cao et al, 2014), and enhanced expression of adhesion molecules (Suzuki et al, 2016). Human microvascular endothelial cells exposed to MWCNT either directly (Cao et al, 2014; Suzuki et al, 2016) or indirectly through co-culture (Snyder-Talkington et al, 2013) with lung epithelial cells respond with increased expression of adhesion molecules and oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Thrombospondin-1 mediates multi-walled carbon nanotube induced impairment of arteriolar dilation

et al. 2017

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Pulmonary exposure to multi-walled carbon nanotubes (MWCNT) has been shown to disrupt endothelium-dependent arteriolar dilation in the peripheral microcirculation. The molecular mechanisms behind these arteriolar disruptions have yet to be fully elucidated. The secreted matricellular matrix protein thrombospondin-1 (TSP-1) is capable of moderating arteriolar vasodilation by inhibiting soluble guanylate cyclase activity. We hypothesized that TSP-1 may be a link between nanomaterial exposure and observed peripheral microvascular dysfunction. To test this hypothesis, wild-type C57B6J (WT) and TSP-1 knockout (KO) mice were exposed via lung aspiration to 50 μg MWCNT or a Sham dispersion medium control. Following exposure (24 h), arteriolar characteristics and reactivity were measured in the gluteus maximus muscle using intravital microscopy (IVM) coupled with microiontophoretic delivery of acetylcholine (ACh) or sodium nitroprusside (SNP). In WT mice exposed to MWCNT, skeletal muscle TSP-1 protein increased > fivefold compared to Sham exposed, and exhibited a 39% and 47% decrease in endothelium-dependent and -independent vasodilation, respectively. In contrast, TSP-1 protein was not increased following MWCNT exposure in KO mice and exhibited no loss in dilatory capacity. Microvascular leukocyte–endothelium interactions were measured by assessing leukocyte adhesion and rolling activity in third order venules. The WT+MWCNT group demonstrated 223% higher leukocyte rolling compared to the WT+Sham controls. TSP-1 KO animals exposed to MWCNT showed no differences from the WT+Sham control. These data provide evidence that TSP-1 is likely a central mediator of the systemic microvascular dysfunction that follows pulmonary MWCNT exposure.

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Section: Discussionmentioning

confidence: 99%

Thrombospondin-1 mediates multi-walled carbon nanotube induced impairment of arteriolar dilation

et al. 2017

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“…In a recent review article, Vietti et al (2016) discuss the key events involved in the lung fibrotic reaction induced by CNTs. These events can include the activation of fibroblasts indirectly through the release of pro-inflammatory and pro-fibrotic mediators by inflammatory cells, induction of oxidative stress, activation of inflammasome or NF-kB (Nuclear Factor Of Kappa Light Polypeptide Gene Enhancer In B-Cells), or the direct induction of fibroblast proliferation, differentiation, and collagen production via signaling by ERK 1/2 (Mitogen-Activated Protein Kinases 1 and 2) or Smad (a family of proteins, named for their similarity to the Drosophila gene Mothers Against Decapentaplegic, Mad).…”

Section: Hypotheses On the Mechanistic Events Related To Genotoxicitymentioning

confidence: 99%

Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans

Kuempel

Jaurand

Møller

et al. 2016

Critical Reviews in Toxicology

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In an evaluation of carbon nanotubes (CNTs) for the IARC Monograph 111, the Mechanisms Subgroup was tasked with assessing the strength of evidence on the potential carcinogenicity of CNTs in humans. The mechanistic evidence was considered to be not strong enough to alter the evaluations based on the animal data. In this paper, we provide an extended, in-depth examination of the in vivo and in vitro experimental studies according to current hypotheses on the carcinogenicity of inhaled particles and fibers. We cite additional studies of CNTs that were not available at the time of the IARC meeting in October 2014, and extend our evaluation to include carbon nanofibers (CNFs). Finally, we identify key data gaps and suggest research needs to reduce uncertainty. The focus of this review is on the cancer risk to workers exposed to airborne CNT or CNF during the production and use of these materials. The findings of this review, in general, affirm those of the original evaluation on the inadequate or limited evidence of carcinogenicity for most types of CNTs and CNFs at this time, and possible carcinogenicity of one type of CNT (MWCNT-7). The key evidence gaps to be filled by research include: investigation of possible associations between in vitro and early-stage in vivo events that may be predictive of lung cancer or mesothelioma, and systematic analysis of dose–response relationships across materials, including evaluation of the influence of physico-chemical properties and experimental factors on the observation of nonmalignant and malignant endpoints.

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“…Several excellent reviews have been published to sum up the biological effects, the overall mode of action, and the interrelations between the physicochemical properties and the bioactivities of CNTs from a toxicological point of view [17–19, 42]. However, the cellular and molecular basis underlying the fibrotic response to CNTs, which is key to understanding the adverse health effects from CNT exposure, remains a topic of considerable challenge.…”

Section: Introductionmentioning

confidence: 99%

Myofibroblasts and lung fibrosis induced by carbon nanotube exposure

Dong

2016

Part Fibre Toxicol

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Carbon nanotubes (CNTs) are newly developed materials with unique properties and a range of industrial and commercial applications. A rapid expansion in the production of CNT materials may increase the risk of human exposure to CNTs. Studies in rodents have shown that certain forms of CNTs are potent fibrogenic inducers in the lungs to cause interstitial, bronchial, and pleural fibrosis characterized by the excessive deposition of collagen fibers and the scarring of involved tissues. The cellular and molecular basis underlying the fibrotic response to CNT exposure remains poorly understood. Myofibroblasts are a major type of effector cells in organ fibrosis that secrete copious amounts of extracellular matrix proteins and signaling molecules to drive fibrosis. Myofibroblasts also mediate the mechano-regulation of fibrotic matrix remodeling via contraction of their stress fibers. Recent studies reveal that exposure to CNTs induces the differentiation of myofibroblasts from fibroblasts in vitro and stimulates pulmonary accumulation and activation of myofibroblasts in vivo. Moreover, mechanistic analyses provide insights into the molecular underpinnings of myofibroblast differentiation and function induced by CNTs in the lungs.In view of the apparent fibrogenic activity of CNTs and the emerging role of myofibroblasts in the development of organ fibrosis, we discuss recent findings on CNT-induced lung fibrosis with emphasis on the role of myofibroblasts in the pathologic development of lung fibrosis. Particular attention is given to the formation and activation of myofibroblasts upon CNT exposure and the possible mechanisms by which CNTs regulate the function and dynamics of myofibroblasts in the lungs. It is evident that a fundamental understanding of the myofibroblast and its function and regulation in lung fibrosis will have a major influence on the future research on the pulmonary response to nano exposure, particle and fiber-induced pneumoconiosis, and other human lung fibrosing diseases.

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Mechanisms of lung fibrosis induced by carbon nanotubes: towards an Adverse Outcome Pathway (AOP)

Cited by 125 publications

References 97 publications

Thrombospondin-1 mediates multi-walled carbon nanotube induced impairment of arteriolar dilation

Thrombospondin-1 mediates multi-walled carbon nanotube induced impairment of arteriolar dilation

Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans

Myofibroblasts and lung fibrosis induced by carbon nanotube exposure

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