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Systematic analysis of multiwalled carbon nanotube-induced cellular signaling and gene expression in human small airway epithelial cells.

ABSTRACT: Multiwalled carbon nanotubes (MWCNT) are one of the most commonly produced nanomaterials, and pulmonary exposure during production, use, and disposal is a concern for the developing nanotechnology field. The airway epithelium is the first line of defense against inhaled particles. In a mouse model, MWCNT were reported to reach the alveolar space of the lung after in vivo exposure, penetrate the epithelial lining, and result in inflammation and progressive fibrosis. This study sought to determine the cellular and gene expression changes in small airway epithelial cells (SAEC) after in vitro exposure to MWCNT in an effort to elucidate potential toxicity mechanisms and signaling pathways. A direct interaction between SAEC and MWCNT was confirmed by both internalization of MWCNT and interaction at the cell periphery. Following exposure, SAEC showed time-dependent increases in reactive oxygen species production, total protein phosphotyrosine and phosphothreonine levels, and migratory behavior. Analysis of gene and protein expression suggested altered regulation of multiple biomarkers of lung damage, carcinogenesis, and tumor progression, as well as genes involved in related signaling pathways. These results demonstrate that MWCNT exposure resulted in the activation of SAEC. Gene expression data derived from MWCNT exposure provide information that may be used to elucidate the underlying mode of action of MWCNT in the small airway and suggest potential prognostic gene signatures for risk assessment.

SUBMITTER: Snyder-Talkington BN

PROVIDER: S-EPMC3627550 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Systematic analysis of multiwalled carbon nanotube-induced cellular signaling and gene expression in human small airway epithelial cells.

Snyder-Talkington Brandi N BN Pacurari Maricica M Dong Chunlin C Leonard Stephen S SS Schwegler-Berry Diane D Castranova Vincent V Qian Yong Y Guo Nancy L NL

Toxicological sciences : an official journal of the Society of Toxicology 20130201 1

Multiwalled carbon nanotubes (MWCNT) are one of the most commonly produced nanomaterials, and pulmonary exposure during production, use, and disposal is a concern for the developing nanotechnology field. The airway epithelium is the first line of defense against inhaled particles. In a mouse model, MWCNT were reported to reach the alveolar space of the lung after in vivo exposure, penetrate the epithelial lining, and result in inflammation and progressive fibrosis. This study sought to determine ...[more]

PMID: 23377615

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Project description:Rationale: Multiwalled carbon nanotubes (MWCNTs) are a potential risk for pulmonary fibrosis because of their fiber-like shape; other physicochemical features, such as rigidity, could also confer fibrogenicity. The signal transducer and activator of transcription 1 (STAT1) is an important antifibrogenic transcription factor that promotes fibroblast growth arrest. STAT1-deficient (Stat1?/?) mice are susceptible to pulmonary fibrosis. Objectives: In this study, we hypothesized that Stat1?/? mice exhibit a differential fibrogenic response to tangled MWCNTs versus rigid MWCNTs above that seen with wild-type (Stat1+/+) mice. Methods:Stat1+/+ and Stat1?/? mice were exposed to tangled MWCNTs or rigid MWCNTs (4 mg/kg) via oropharyngeal aspiration, and lung tissues were collected after 1 and 21 days to measure messenger RNA and protein levels of fibrogenic mediators. Results: Compared with tangled MWCNTs, rigid MWCNTs caused mucous cell metaplasia, epithelial cell proliferation, increased fibrosis, and larger granulomas in the lungs of mice. Both MWCNT types induced acute neutrophilia; however, only rigid MWCNTs induced chronic neutrophilia. Stat1?/? mice exhibited higher serum levels of immunoglobin E and even higher levels when treated with rigid MWCNTs. Twenty-one days after treatment with rigid MWCNTs, compared with Stat1+/+ mice, Stat1?/? mice had higher levels of transforming growth factor-?1 (TGF-?1) protein in bronchoalveolar lavage fluid, increased transforming growth factor-?1 signaling activation, and higher airway collagen deposition. Some of the results of this study were previously reported in the form of an abstract and a paper (1, 2). Conclusions: Our data emphasize that rigid MWCNTs produce much stronger immune and fibrogenic responses than tangled MWCNTs and that these effects are exaggerated by STAT1 deficiency, highlighting the importance of tube rigidity and genetic susceptibility. The mechanism of STAT1 susceptibility to MWCNTs-induced fibrosis appears to be through dysregulated transforming growth factor-?1 production and signaling.

Dataset Information

Systematic analysis of multiwalled carbon nanotube-induced cellular signaling and gene expression in human small airway epithelial cells.

Publications

Systematic analysis of multiwalled carbon nanotube-induced cellular signaling and gene expression in human small airway epithelial cells.

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