Search

Hong Xue,1,2 Baosong Xie,1,2 Nengluan Xu,1,2 Hongru Li,1,2 Qianshun Chen,2,3 Weiping Xie,4 Hong Wang4 1Department of Respiratory and Critical Care Medicine, Fujian Provincial Hospital, Fuzhou, Fujian, People’s Republic of China; 2Provincial School of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 3Department of Thoracic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of ChinaCorrespondence: Baosong Xie; Hong XueDepartment of Respiratory and Critical Care Medicine, Fujian Provincial Hospital, No. 134, East Street, Fuzhou, Fujian, 350000, People’s Republic of ChinaTel +86 591-88217531Email xiebaos_baosong@163.com; xuehong_xhx@163.comPurpose: Etanercept (ETN), a tumor necrosis factor-α (TNF-α) inhibitor, has been applied in the treatment of many diseases. However, whether it has effects on chronic obstructive pulmonary disease (COPD) and its interaction with tumor necrosis factor receptor 1 (TNFR1) remained unknown.Methods: Histopathological analysis of lung tissues from non-smokers and smokers with or without COPD was conducted using hematoxylin–eosin (H&E) staining, Van Gieson (VG) staining, and terminal transferase-mediated biotin dUTP nick end labeling (TUNEL). TNF-α content was measured using Immunohistochemistry. Correlation analysis among apoptosis rate, smoke index, the FEV1/FVC ratio, and TNF-α-positive cells was performed. After ETN treatment and transfection of overexpressed or silenced TNFR1, levels of inflammatory cytokines, apoptosis and related genes expressions in cigarette smoke extract (CSE)-treated human pulmonary artery endothelial cells (HPAECs) were detected using enzyme-linked immunosorbent assay (ELISA), Hoechst 33342 staining, flow cytometry, quantitative real-time PCR (qRT-PCR) and Western blot.Results: Pulmonary arterial remodeling and increased apoptotic and TNF-α+ HPAECs were found in lung tissue of smokers with or without COPD, with higher degrees in smokers with COPD. The numbers of apoptotic and TNF-α+ HPAECs were positively correlated with smoke index, while the FEV1/FVC ratio was negatively correlated with apoptotic HPAECs. In HPAECs, ETN downregulated the expressions of proteins related to CSE-induced apoptosis and the TNF receptor family, decreased CSE-induced cell apoptosis and inflammatory cytokine levels, and inhibited TNFR1 expression and p65 phosphorylation. Overexpressed TNFR1 reversed the effects of ETN on CSE-treated HPAECs, whereas silencing TNFR1 did the opposite.Conclusion: ETN protected HPAECs against CSE-induced inflammation and apoptosis via downregulating TNFR1, thus providing a potential therapy for smoking-induced COPD.Keywords: chronic obstructive pulmonary disease, etanercept, apoptosis, cigarette smoke extract, human pulmonary artery endothelial cells, tumor necrosis factor receptor 1