International Journal of COPD (May 2021)

Etanercept Protected Against Cigarette Smoke Extract-Induced Inflammation and Apoptosis of Human Pulmonary Artery Endothelial Cells via Regulating TNFR1

  • Xue H,
  • Xie B,
  • Xu N,
  • Li H,
  • Chen Q,
  • Xie W,
  • Wang H

Journal volume & issue
Vol. Volume 16
pp. 1329 – 1345

Abstract

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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 [email protected]; [email protected]: 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

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