Thioredoxin overexpression modulates remodeling factors in stress responses to cigarette smoke.
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)-beta1, 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-beta1, EGFR, and p21 and upregulation of MMP-9 expression. TGF-beta1 was shown to regulate MMP-9 as evidenced by suppression of MMP-9 protein induction by TGF-beta1 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.
Institute of Environmental Health, College of Public Health, National Taiwan University, Taipei.
Yi-Ling
YL
Huang
Chun-Yu
CY
Chuang
Fung-Chang
FC
Sung
Chia-Yang
CY
Chen
D001980:Bronchi / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival; D004847:Epithelial Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects; D015208:Smoke Inhalation Injury; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014026:Nicotiana / Q000009:adverse effects
D017382:Reactive Oxygen Species; D012906:Smoke; D013879:Thioredoxins