Journal of toxicology and environmental health. Part A
Paging:
Volume 71 (2008) nr. 22 pages 1490-1498
Year:
2008-01
Contents:
Cigarette smoke (CS) generates reactive oxygen species (ROS) to produce oxidative damage of bronchial epithelial cells. Prolonged repair responses lead to airway remodeling and irreversible airflow limitation. Thioredoxin (TRX) is a redox protein that scavenges ROS to prevent oxidative stress. The aim of this study was to investigate the mechanisms underlying TRX-mediated CS-induced stress relevant to airway remodeling. Results showed that CS stimulated ROS generation and apoptosis in normal human bronchial epithelial (BEAS-2B) cells, and interfered with gene expression of remodeling factors, such as activation of transforming growth factor (TGF)-β1, epidermal growth factor receptor (EGFR), and cyclin-dependent kinase inhibitor (p21), but repressed matrix metalloproteinases (MMP)-9. In particular, TRX-overexpressing bronchial epithelial (TRX-TD) cells reduced CS-induced apoptosis, and suppressed airway remodeling through attenuation of TGF-β1, EGFR, and p21 and upregulation of MMP-9 expression. TGF-β1 was shown to regulate MMP-9 as evidenced by suppression of MMP-9 protein induction by TGF-β1 antibody. In addition, CS produced apoptosis of BEAS-2B cells via TRX oxidation, which activated signal transduction factors, including apoptosis signal-regulating kinase (ASK) 1 and c-Jun N-terminal kinase (JNK). In contrast, TRX-TD cells exposed to CS retained reduced-form TRX, and inactivated ASK1 and JNK to attenuate apoptosis. This study indicated TRX overexpression was involved in CS-induced apoptosis and prevented airway remodeling through ASK1-JNK inactivation and MMP-9 augmentation.