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: Wan-Yu Hsieh, Cheng-Chung Chou, Chao-Chi Ho, Sung-Liang Yu, Hsuan-Yu Chen, Han-Yi E Chou, Jeremy J W Chen, Huei-Wen Chen, Pan-Chyr Yang
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 46 Issue 2 Pg. 257-67 (Feb 2012) ISSN: 1535-4989 [Electronic] United States
• PMID: 21960547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nanotubes, Carbon

Topics

• Animals
• Bronchial Hyperreactivity (metabolism, pathology)
• Bronchoalveolar Lavage Fluid
• Coculture Techniques
• Gene Expression Profiling
• Lung (metabolism, pathology)
• Male
• Mice
• Mice, Inbred ICR
• Nanotubes, Carbon
• Transcriptome
• Up-Regulation