Shvedova, A. A. et al. Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 289, L698-L708

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
AJP Lung Cellular and Molecular Physiology (Impact Factor: 4.08). 12/2005; 289(5):L698-708. DOI: 10.1152/ajplung.00084.2005
Source: PubMed


Single-walled carbon nanotubes (SWCNT) are new materials of emerging technological importance. As SWCNT are introduced into the life cycle of commercial products, their effects on human health and environment should be addressed. We demonstrated that pharyngeal aspiration of SWCNT elicited unusual pulmonary effects in C57BL/6 mice that combined a robust but acute inflammation with early onset yet progressive fibrosis and granulomas. A dose-dependent increase in the protein, LDH, and gamma-glutamyl transferase activities in bronchoalveolar lavage were found along with accumulation of 4-hydroxynonenal (oxidative biomarker) and depletion of glutathione in lungs. An early neutrophils accumulation (day 1), followed by lymphocyte (day 3) and macrophage (day 7) influx, was accompanied by early elevation of proinflammatory cytokines (TNF-alpha, IL-1beta; day 1) followed by fibrogenic transforming growth factor (TGF)-beta1 (peaked on day 7). A rapid progressive fibrosis found in mice exhibited two distinct morphologies: 1) SWCNT-induced granulomas mainly associated with hypertrophied epithelial cells surrounding SWCNT aggregates and 2) diffuse interstitial fibrosis and alveolar wall thickening likely associated with dispersed SWCNT. In vitro exposure of murine RAW 264.7 macrophages to SWCNT triggered TGF-beta1 production similarly to zymosan but generated less TNF-alpha and IL-1beta. SWCNT did not cause superoxide or NO.production, active SWCNT engulfment, or apoptosis in RAW 264.7 macrophages. Functional respiratory deficiencies and decreased bacterial clearance (Listeria monocytogenes) were found in mice treated with SWCNT. Equal doses of ultrafine carbon black particles or fine crystalline silica (SiO2) did not induce granulomas or alveolar wall thickening and caused a significantly weaker pulmonary inflammation and damage.

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    • "Recent studies show that micro-and nano-sized substances may have significant pathological effects on humans (Lim et al., 2012; Golokhvast et al., 2015a,b). The toxic effects of multi-walled carbon nanotubes (MWCNTs) have been studied for several years and adverse responses have been identified in several tissues, including cytotoxicity in keratinocyte cells (Shvedova et al., 2003) and inflammatory and fibrogenic responces in pulmonary tissues (Shvedova et al., 2005). It has been also found that MWCNTs produce a time-and dose-dependent toxic response upon reaching the lungs in sufficient quantity (Helland et al., 2007). "

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    • "As some nanoparticles dissolve , they can release toxic ions that can damage the lung tissue, making dissolution rate an important characteristic that affects lung inflammation (Cho et al., 2011Cho et al., , 2012aCho et al., , 2012bDonaldson et al., 2013;Nel et al., 2009). Fibre-shaped materials are more toxic to the lungs compared to spherical shaped nanoparticles of the same chemical composition (Porter et al., 2013;Shvedova et al., 2005;Stoehr et al., 2011). In general, cationic nanoparticles are easily taken up by cells and more cytotoxic than neutral or anionic nanoparticles (Choi et al., 2010;Hornung et al., 2008;Yazdi et al., 2010;Zhang et al., 2011;Asati et al., 2010;Nagy et al., 2012). "
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    ABSTRACT: The rapidly expanding manufacturing, production and use of nanomaterials has raised concerns for both worker and consumer safety. Various studies have been published in which induction of pulmonary inflammation after inhalation exposure to nanomaterials has been described. Nanomaterials can vary in aspects such as size, shape, charge, crystallinity, chemical composition, and dissolution rate. Currently, efforts are made to increase the knowledge on the characteristics of nanomaterials that can be used to categorise them into hazard groups according to these characteristics. Grouping helps to gather information on nanomaterials in an efficient way with the aim to aid risk assessment. Here, we discuss different ways of grouping nanomaterials for their risk assessment after inhalation. Since the relation between single intrinsic particle characteristics and the severity of pulmonary inflammation is unknown, grouping of nanomaterials by their intrinsic characteristics alone is not sufficient to predict their risk after inhalation. The biokinetics of nanomaterials should be taken into account as that affects the dose present at a target site over time. The parameters determining the kinetic behaviour are not the same as the hazard-determining parameters. Furthermore, characteristics of nanomaterials change in the life-cycle, resulting in human exposure to different forms and doses of these nanomaterials. As information on the biokinetics and in situ characteristics of nanomaterials is essential but often lacking, efforts should be made to include these in testing strategies. Grouping nanomaterials will probably be of the most value to risk assessors when information on intrinsic characteristics, life-cycle, biokinetics and effects are all combined.
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    • "In recent years, some types of ENMs have been shown to be hazardous to human health. It has been reported that carbon nanotubes (CNTs) are capable of inducing reactive oxygen species (ROS) (Sharma et al., 2007) and pulmonary effects (Shvedova et al., 2005). Toxicological studies have also shown that nanosized titanium dioxide (TiO 2 ) particles have the potential to induce cytotoxic (Saquib et al., 2012; Setyawati et al., 2012), genotoxic (Shukla et al., 2011; Trouiller, Reliene, Westbrook, Solaimani, & Schiestl, 2009), and inflammatory (Grassian, O'Shaughnessy, Adamcakova-Dodd, Pettibone, & Thorne, 2007; Han, Newsome, & Hennig, 2013) effects. "
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    ABSTRACT: There is increasing recognition that some nanomaterials may pose a risk to human health and the environment. Moreover, the industrial use of the novel engineered nanomaterials (ENMs) increases at a higher rate than data generation for hazard assessment; consequently, many of them remain untested. The large number of nanomaterials and their variants (e.g., different sizes and coatings) requiring testing and the ethical pressure towards nonanimal testing means that in a first instance, expensive animal bioassays are precluded, and the use of (quantitative) structure–activity relationships ((Q)SARs) models as an alternative source of (screening) hazard information should be explored. (Q)SAR modelling can be applied to contribute towards filling important knowledge gaps by making best use of existing data, prioritizing the physicochemical parameters driving toxicity, and providing practical solutions for the risk assessment problems caused by the diversity of ENMs. This paper covers the core components required for successful application of (Q)SAR methods to ENM toxicity prediction, summarizes the published nano-(Q)SAR studies, and outlines the challenges ahead for nano-(Q)SAR modelling. It provides a critical review of (1) the present availability of ENM characterization/toxicity data, (2) the characterization of nanostructures that meet the requirements for (Q)SAR analysis, (3) published nano-(Q)SAR studies and their limitations, (4) in silico tools for (Q)SAR screening of nanotoxicity, and (5) prospective directions for the development of nano-(Q)SAR models.
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