title: Single-walled carbon nanotubes induce airway hyperreactivity and parenchymal injury in mice.
abstract: Inhalation of single-walled carbon nanotubes (SWCNTs) has raised serious concerns related to potential toxic effects in the respiratory system. This study examined possible SWCNT-induced toxic mechanisms in vivo in mice. The results indicated that a single intratracheal instillation of SWCNTs could induce airway hyperreactivity and airflow obstruction and confirmed previous findings of granulomatous changes in the lung parenchyma that persisted from 7 days to 6 months after exposure. The irreversible lung pathology and functional airway alterations in the mouse model mimicked obstructive airway disease in humans. Transcriptomic analysis showed that SWCNTs might up-regulate proteinases (cathepsin K and matrix metalloproteinase [MMP]12), chemokines C-C motif ligands (CCL2 and CCL3), and several macrophage receptors (Toll-like receptor 2, macrophage scavenger receptor 1). Pathway analyses showed that NF-κB-related inflammatory responses and downstream signals affecting tissue remodeling dominated the pathologic process. The NF-κB inhibitor pyrrolidine dithiocarbamate attenuated SWCNT-induced airway hyperreactivity, chronic airway inflammation, and MMP12 and cathepsin K expression when administered in vivo, whereas a cathepsin K inhibitor could partially reduce airway hyperreactivity and granulomatous changes in the SWCNT-treated group. The up-regulation of cathepsin K and MMP12 by SWCNTs was further confirmed via in vitro coculture of bronchoalveolar macrophages with lung epithelial/mesenchymal cells but not in macrophages without coculture, indicating that SWCNT-induced MMP12 and cathespin K were cell-type specific and cell-cell interaction dependent. In conclusion, exposure to SWCNTs may cause irreversible obstructive airway disease. Nanotoxicogenomics uncovered novel mechanisms underlying SWCNT-induced lung diseases, implicating MMP12 and cathepsin K in the pathologic injury as potential biomarkers or therapeutic targets.
authors.affiliation: Graduate Institute of Toxicology, National Taiwan University College of Medicine, No. 1 Sec. 1 Ren-Ai Road, Taipei, Taiwan.
authors.forename: Wan-Yu
authors.initials: WY
authors.lastname: Hsieh
authors.forename: Cheng-Chung
authors.initials: CC
authors.lastname: Chou
authors.forename: Chao-Chi
authors.initials: CC
authors.lastname: Ho
authors.forename: Sung-Liang
authors.initials: SL
authors.lastname: Yu
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Chen
authors.forename: Han-Yi E
authors.initials: HY
authors.lastname: Chou
authors.forename: Jeremy J W
authors.initials: JJ
authors.lastname: Chen
authors.forename: Huei-Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000378:metabolism / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid; D018920:Coculture Techniques; D020869:Gene Expression Profiling; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D037742:Nanotubes, Carbon; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D037742:Nanotubes, Carbon