Signal Transducer and Activator of Transcription 1 Regulates Multiwalled Carbon Nanotube–induced Pulmonary Fibrosis in Mice via Suppression of Transforming Growth Factor-β1 Production and Signaling

Abstract

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-beta1 (TGF-beta1) protein in bronchoalveolar lavage fluid, increased transforming growth factor-beta1 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-beta1 production and signaling.