Single-walled carbon nanotubes induce airway hyperreactivity and parenchymal injury in mice
Journal
American Journal of Respiratory Cell and Molecular Biology
Journal Volume
46
Journal Issue
2
Pages
257-267
Date Issued
2012
Author(s)
Hsieh W.-Y.
Chou C.-C.
Chen H.-Y.
Chen J.J.W.
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. Copyright ? 2012 by the American Thoracic Society.
Other Subjects
cathepsin K; cathepsin K inhibitor; cutaneous T cell attracting chemokine; macrophage elastase; macrophage inflammatory protein 1alpha; pentoxifylline; pyrrolidine dithiocarbamate; single walled nanotube; toll like receptor 2; airway hyperreactivity; airway inflammation; airway obstruction; animal experiment; animal model; article; cell interaction; controlled study; gene expression; in vivo study; inflammation; lung disease; lung injury; macrophage; male; mesenchyme cell; mouse; nonhuman; obstructive airway disease; upregulation; Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Coculture Techniques; Gene Expression Profiling; Lung; Male; Mice; Mice, Inbred ICR; Nanotubes, Carbon; Transcriptome; Up-Regulation; Mus
Type
journal article