Etanercept protected against cigarette smoke extract-induced inflammation and apoptosis of human pulmonary artery endothelial cells via regulating TNFR1

Purpose: 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 apop-tosis 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.