Selenite selectively kills lung fibroblasts to treat bleomycin-induced pulmonary fibrosis
Jiun-Han Lin,
Chen-Chi Liu,
Chao-Yu Liu,
Tien-Wei Hsu,
Yi-Chen Yeh,
Chorng-Kuang How,
Han-Shui Hsu,
Shih-Chieh Hung
Affiliations
Jiun-Han Lin
Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
Chen-Chi Liu
Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Traumatology, Emergency Department, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Chao-Yu Liu
Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Far-Eastern Memorial Hospital, New Taipei City, Taiwan
Tien-Wei Hsu
Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
Yi-Chen Yeh
Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
Chorng-Kuang How
Division of Traumatology, Emergency Department, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Han-Shui Hsu
Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; Corresponding author. Division of Thoracic Surgery, Taipei Veterans General Hospital, Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, No. 201, Sec. 2, Shih-Pai Road, Beitou District, Taipei, 11217, Taiwan.
Shih-Chieh Hung
Drug Development Center, Institute of Translational Medicine and New Drug Development, School of Medicine, Taiwan; College of Life Sciences, China Medical University, Taichung, Taiwan; Integrative Stem Cell Center, Department of Orthopedics, China Medical University Hospital, Taichung, Taiwan; Corresponding author. College of Life Sciences, Drug Development Center, Institute of Translational Medicine and New Drug Development, School of Medicine, China Medical University, Integrative Stem Cell Center, China Medical University Hospital, 7F, No. 6, Xueshi Rd., North Dist., Taichung, 404, Taiwan.
Background: Interstitial lung disease (ILD) treatment is a critical unmet need. Selenium is an essential trace element for human life and an antioxidant that activates glutathione, but the gap between its necessity and its toxicity is small and requires special attention. Whether selenium can be used in the treatment of ILD remains unclear. Methods: We investigated the prophylactic and therapeutic effects of selenite, a selenium derivative, in ILD using a murine model of bleomycin-induced idiopathic pulmonary fibrosis (IPF). We further elucidated the underlying mechanism using in vitro cell models and examined their relevance in human tissue specimens. The therapeutic effect of selenite in bleomycin-administered mice was assessed by respiratory function and histochemical changes. Selenite-induced apoptosis and reactive oxygen species (ROS) production in murine lung fibroblasts were measured. Results: Selenite, administered 1 day (inflammation phase) or 8 days (fibrotic phase) after bleomycin, prevented and treated deterioration of lung function and pulmonary fibrosis in mice. Mechanistically, selenite inhibited the proliferation and induced apoptosis of murine lung fibroblasts after bleomycin treatment both in vitro and in vivo. In addition, selenite upregulated glutathione reductase (GR) and thioredoxin reductase (TrxR) in murine lung fibroblasts, but not in lung epithelial cells, upon bleomycin treatment. GR and TrxR inhibition eliminates the therapeutic effects of selenite. Furthermore, we found that GR and TrxR were upregulated in the human lung fibroblasts of IPF patient samples. Conclusions: Selenite induces ROS production and apoptosis in murine lung fibroblasts through GR and TrxR upregulation, thereby providing a therapeutic effect in bleomycin-induced IPF.
