Pulmonary and Systemic Immune Response to Inhaled Multiwalled Carbon Nanotubes

College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131-0001, USA.
Toxicological Sciences (Impact Factor: 3.85). 12/2007; 100(1):203-14. DOI: 10.1093/toxsci/kfm196
Source: PubMed


Inhalation of multiwalled carbon nanotubes (MWCNTs) at particle concentrations ranging from 0.3 to 5 mg/m3 did not result in significant lung inflammation or tissue damage, but caused systemic immune function alterations. C57BL/6
adult (10- to 12-week) male mice were exposed by whole-body inhalation to control air or 0.3, 1, or 5 mg/m3 respirable aggregates of MWCNTs for 7 or 14 days (6 h/day). Histopathology of lungs from exposed animals showed alveolar
macrophages containing black particles; however, there was no inflammation or tissue damage observed. Bronchial alveolar lavage
fluid also demonstrated particle-laden macrophages; however, white blood cell counts were not increased compared to controls.
MWCNT exposures to 0.3 mg/m3 and higher particle concentrations caused nonmonotonic systemic immunosuppression after 14 days but not after 7 days. Immunosuppression
was characterized by reduced T-cell–dependent antibody response to sheep erythrocytes as well as T-cell proliferative ability
in presence of mitogen, Concanavalin A. Assessment of nonspecific natural killer (NK) cell activity showed that animals exposed
to 1 mg/m3 had decreased NK cell function. Gene expression analysis of selected cytokines and an indicator of oxidative stress were
assessed in lung tissue and spleen. No changes in gene expression were observed in lung; however, interleukin-10 (IL-10) and
NAD(P)H oxidoreductase 1 mRNA levels were increased in spleen.

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Available from: Randy Vander Wal, May 30, 2014
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    • "instillation (0.5–20 µm; 1–100 µg/rat) or inhalation/instillation (10 µm; 50 µg/mouse for i.t. instillation) were not associated with granuloma formation and fibrosis (Elgrabli et al. 2008; Li et al. 2007a; Mitchell et al. 2007). "
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    ABSTRACT: The development of products containing carbon nanotubes (CNTs) is a major achievement of nanotechnology, although concerns regarding risk of toxic effects linger if the hazards associated with these materials are not thoroughly investigated. Exposure to CNTs has been associated with depletion of antioxidants, increased intracellular production of reactive oxygen species and pro-inflammatory signaling in cultured cells with primary function in the immune system as well as epithelial, endothelial and stromal cells. Pre-treatment with antioxidants has been shown to attenuate these effects, indicating a dependency of oxidative stress on cellular responses to CNT exposure. CNT-mediated oxidative stress in cell cultures has been associated with elevated levels of lipid peroxidation products and oxidatively damaged DNA. Investigations of oxidative stress endpoints in animal studies have utilized pulmonary, gastrointestinal, intravenous and intraperitoneal exposure routes, documenting elevated levels of lipid peroxidation products and oxidatively damaged DNA nucleobases especially in the lungs and liver, which to some extent occur concomitantly with altered levels of components in the antioxidant defense system (glutathione, superoxide dismutase or catalase). CNTs are biopersistent high aspect ratio materials, and some are rigid with lengths that lead to frustrated phagocytosis and pleural accumulation. There is accumulating evidence showing that pulmonary exposure to CNTs is associated with fibrosis and neoplastic changes in the lungs, and cardiovascular disease. As oxidative stress and inflammation responses are implicated in the development of these diseases, converging lines of evidence indicate that exposure to CNTs is associated with increased risk of cardiopulmonary diseases through generation of a pro-inflammatory and pro-oxidant milieu in the lungs.
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    • "Recent in vitro studies have indicated the cytotoxicity of MWCNTs in human lung or bronchial epithelial cell culture systems (Cavallo et al., 2012; Haniu et al., 2013; Hirano et al., 2010). The pulmonary toxicity of MWCNTs in in vivo rodent models has also been reported (Ma-Hock et al., 2013; Mitchell et al., 2007; Morimoto et al., 2012a; Porter et al., 2013; Treumann et al., 2013; Urankar et al., 2012). A 90-day inhalation toxicity study with MWCNTs performed according to the Organization for Economic Co-operation and Development (OECD) test guidelines showed that increased lung weights, pronounced multifocal granulomatous inflammation, diffuse histiocytic and neutrophilic inflammation, and intra-alveolar lipoproteinosis were observed in lung and lung-associated lymph nodes at 0.5 mg/m 3 and 2.5 mg/m 3 (Ma-Hock et al., 2009). "
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    ABSTRACT: Abstract The use of carbon nanotubes in the industry has grown; however, little is known about their toxicological mechanism of action. Single-wall carbon nanotube (SWCNT) suspensions were administered by single intratracheal instillation in rats. Persistence of alveolar macrophage-containing granuloma was observed around the sites of SWCNT aggregation at 90 days post-instillation in 0.2-mg- or 0.4-mg-injected doses per rat. Meanwhile, gene expression profiling revealed that a large number of genes involved in the inflammatory response were markedly upregulated until 90 days or 180 days post-instillation. Subsequently, gene expression patterns were dramatically altered at 365 days post-instillation, and the number of upregulated genes involved in the inflammatory response was reduced. These results suggested that alveolar macrophage-containing granuloma reflected a characteristic of the histopathological transition period from the acute-phase to the subchronic-phase of inflammation, as well as pulmonary acute phase response persistence up to 90 or 180 days after intratracheal instillation in this experimental setting. The expression levels of the genes Ctsk, Gcgr, Gpnmb, Lilrb4, Marco, Mreg, Mt3, Padi1, Slc26a4, Spp1, Tnfsf4 and Trem2 were persistently upregulated in a dose-dependent manner until 365 days post-instillation. In addition, the expression levels of Atp6v0d2, Lpo, Mmp7, Mmp12 and Rnase9 were significantly upregulated until 754 days post-instillation. We propose that these persistently upregulated genes in the chronic-phase response following the acute-phase response act as potential biomarkers in lung tissue after SWCNT instillation. This study provides further insight into the time-dependent changes in genomic expression associated with the pulmonary toxicity of SWCNTs.
    Full-text · Article · Jun 2014 · Nanotoxicology
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    • "After inhalation exposure, CNTs induced systemic immunosuppression in mice, including production of prostaglandin and IL-10 [17] [18] and T cell dysfunction [18] [19] [23]. For example, inhalation of CNTs (0.3, 1, or 5 mg/m 3 , 6 h/day, 14 days) hardly induced injury in lungs but resulted in nonmonotonic systemic immunosuppression "
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    ABSTRACT: Nanoparticles (NPs) have promising applications in medicine. Immune system is an important protective system to defend organisms from non-self matters. NPs interact with the immune system and modulate its function, leading to immunosuppression or immunostimulation. These modulating effects may bring benefits or danger. Compositions, sizes, and surface chemistry, and so forth, affect these immunomodulations. Here we give an overview of the relationship between the physicochemical properties of NPs, which are candidates to be applied in medicine, and their immunomodulation properties.
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