Mitochondrial-Targeting Antioxidant SS-31 Suppresses Airway Inflammation and Oxidative Stress Induced by Cigarette Smoke.

Yong-Chun Shen,Li-Juan Gao,De-Qing Yang,Liu Lian,Vinicius De Frias Carvalho,Tao Wang,Fu-Qiang Wen,Dan Xu,Qiu-Nan Zuo,Lei Chen,Chun Wan

doi:10.1155/2021/6644238

Abstract

This study investigated whether the mitochondrial-targeted peptide SS-31 can protect against cigarette smoke- (CS-) induced airway inflammation and oxidative stress in vitro and in vivo. Mice were exposed to CS for 4 weeks to establish a CS-induced airway inflammation model, and those in the experimental group were pretreated with SS-31 1 h before CS exposure. Pathologic changes and oxidative stress in lung tissue, inflammatory cell counts, and proinflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. The mechanistic basis for the effects of SS-31 on CS extract- (CSE-) induced airway inflammation and oxidative stress was investigated using BEAS-2B bronchial epithelial cells and by RNA sequencing and western blot analysis of lung tissues. SS-31 attenuated CS-induced inflammatory injury of the airway and reduced total cell, neutrophil, and macrophage counts and tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, and matrix metalloproteinase (MMP) 9 levels in BALF. SS-31 also attenuated CS-induced oxidative stress by decreasing malondialdehyde (MDA) and myeloperoxidase (MPO) activities and increasing that of superoxide dismutase (SOD). It also reversed CS-induced changes in the expression of mitochondrial fission protein (MFF) and optic atrophy (OPA) 1 and reduced the amount of cytochrome c released into the cytosol. Pretreatment with SS-31 normalized TNF-α, IL-6, and MMP9 expression, MDA and SOD activities, and ROS generation in CSE-treated BEAS-2B cells and reversed the changes in MFF and OPA1 expression. RNA sequencing and western blot analysis showed that SS-31 inhibited CS-induced activation of the mitogen-activated protein kinase (MAPK) signaling pathway in vitro and in vivo. Thus, SS-31 alleviates CS-induced airway inflammation and oxidative stress via modulation of mitochondrial function and regulation of MAPK signaling and thus has therapeutic potential for the treatment of airway disorders caused by smoking.

Highlights

Cigarette smoke (CS) contains thousands of toxins and is one of the most important risk factors for the development of chronic obstructive pulmonary disease (COPD), a progressive lung condition characterized by persistent airway inflammation and irreversible restriction of airflow [1, 2]
Neutrophil, and macrophage counts in mouse bronchoalveolar lavage fluid (BALF) were increased in cigarette smoke- (CS-)exposed mice, which was abrogated by pretreatment with SS-31 (Figures 1(a)–1(c))
To confirm the in vivo finding that SS-31 attenuated CS-induced inflammation and oxidative stress via inhibition of P38 mitogen-activated protein kinase (MAPK) signaling and to more closely examine the underlying mechanism, we evaluated the effects of anisomycin on BEAS-2B cells pretreated with CS Extract (CSE) and SS31

Summary

Introduction

Cigarette smoke (CS) contains thousands of toxins and is one of the most important risk factors for the development of chronic obstructive pulmonary disease (COPD), a progressive lung condition characterized by persistent airway inflammation and irreversible restriction of airflow [1, 2]. CS induces chronic airway inflammation, airway mucus hypersecretion, and oxidative stress, leading to clinically significant mechanical obstruction of small airways, reduced airflow, and a progressive decline in lung function [5, 6]. Mitochondria are the organelles responsible for energy metabolism and play an important role in maintaining cell function. Recent studies have suggested that CS can cause mitochondrial dysfunction and trigger inflammatory responses and oxidative stress, which are linked to COPD [7, 8]. SS-31, a novel mitochondrial-targeting antioxidant compound, can eliminate reactive oxygen species (ROS) and increase ATP production in mitochondria,

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Results

Conclusion