Effect of lentivirus-mediated CFTR overexpression on oxidative stress injury and inflammatory response in the lung tissue of COPD mouse model.

Xiaoli Xu,Xiaoyue Shen,Xiangyi Yin,Huimin Huang,Hongmei Fang

doi:10.1042/bsr20193667

Abstract

We aimed to investigate the regulatory mechanism of lentivirus-mediated overexpression of cystic fibrosis transmembrane conductance regulator (CFTR) in oxidative stress injury and inflammatory response in the lung tissue of mouse model of chronic obstructive pulmonary disease (COPD). COPD mouse model induced by cigarette smoke was established and normal mice were used as control. The mice were assigned into a normal group (control), a model group (untreated), an oe-CFTR group (injection of lentivirus overexpressing CFTR), and an oe-NC group (negative control, injection of lentivirus expressing irrelevant sequences). Compared with the oe-NC group, the oe-CFTR group had higher CFTR expression and a better recovery of pulmonary function. CFTR overexpression could inhibit the pulmonary endothelial cell apoptosis, reduce the levels of glutathione (GSH), reactive oxygen species (ROS), and malondialdehyde (MDA) and increase the values of superoxide dismutase (SOD), GSH peroxidase (GSH-Px), and total antioxidant capacity (T-AOC). The overexpression also led to reductions in the white blood cell (WBC) count in alveolus pulmonis, the concentrations of C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor-α, and the protein expressions of NF-κB p65, ERK, JNK, p-EPK, and p-JNK related to MAPK/NF-κB p65 signaling pathway. In conclusion, CFTR overexpression can protect lung tissues from injuries caused by oxidative stress and inflammatory response in COPD mouse model. The mechanism behind this may be related to the suppression of MAPK/NF-κB p65 signaling pathway.

Highlights

Chronic obstructive pulmonary disease (COPD) is a type of chronic lung disease characterized by persistent and incomplete reversible airflow restriction in airway and slow degeneration in pulmonary function [1,2]
Mice used for modeling had higher RI level and lower dynamic lung compliance (Cdyn), peak inspiratory flow (PIF), and peak expiratory flow (PEF) levels compared with the normal group
Approximately 600 million people are suffering from COPD worldwide, and the burden of COPD will rank fifth in global burden of disease by 2020 [11]

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a type of chronic lung disease characterized by persistent and incomplete reversible airflow restriction in airway and slow degeneration in pulmonary function [1,2]. Clinical manifestations of COPD include respiratory muscle atrophy and decreased contractility, endurance, and defense function of the lung [3]. It is generally believed that the disease is the result of actions by both environmental (extrinsic) factors and hereditary (intrinsic) factors. Environmental (extrinsic) factors mainly include smoking, inhalation of dust and chemicals, air pollution, respiratory tract infection, and exposure to biological dye. Hereditary (intrinsic) factors include lack of α1-antitrypsin and aberrant gene expressions of glutathione (GSH) S-transferase gene, and interleukin (IL)-10. Oxidative stress is one of the key components in the pathogenesis of COPD. It can damage the lung tissue directly and cause oxidative inactivation of protease, exudation of inflammatory cells, and gene expression of proinflammatory mediator, thereby promoting the occurrence and development of COPD.

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