Cigarette smoke exposure induces ROS-mediated autophagy by regulating sestrin, AMPK, and mTOR level in mice

Ana Lucia Bernardo Carvalho Morsch,Elvis Wisniewski,Thais Fernandes Luciano,Vitor Hugo Comin,Gustavo De Bem Silveira,Scherolin De Oliveira Marques,Anand Thirupathi,Paulo Cesar Silveira Lock,Claudio Teodoro De Souza

doi:10.1080/13510002.2019.1601448

Ana Lucia Bernardo Carvalho Morsch, Elvis Wisniewski + Show 7 more

Open Access

https://doi.org/10.1080/13510002.2019.1601448

Copy DOI

Abstract

ABSTRACTMany pathological conditions linked to cigarette smoking are caused by the production of reactive oxygen species (ROS). The present study was conducted to analyze the effect of ROS on the lungs of Swiss mice exposed to cigarette smoking, focusing on autophagy-mediated mechanisms, and investigate the involvement of SESN2, AMPK, and mTOR signaling. Mice were exposed to cigarette smoke (CS) for 7, 15, 30, 45, and 60 days; the control group was not exposed to CS. Only mice exposed to CS for 45 days were selected for subsequent N-acetylcysteine (NAC) supplementation and smoke cessation analyses. Exposure to CS increased the production of ROS and induced molecular changes in the autophagy pathway, including an increase in phosphorylated AMPK and ULK1, reduction in phosphorylated mTOR, and increases in SESN2, ATG12, and LC3B levels. NAC supplementation reduced ROS levels and reversed all molecular changes observed upon CS treatment, suggesting the involvement of oxidative stress in inducing autophagy upon CS exposure. When exposure to CS was stopped, there were decreases in the levels of oxidative stress, AMPK and ULK1 phosphorylation, and autophagy-initiating molecules and increase in mTOR phosphorylation. In conclusion, these results suggest the involvement of ROS, SESN2, AMPK, and mTOR in the CS-induced autophagic process in the lung.

Highlights

The human airway system is continuously exposed to numerous chemical toxicants, which lead to pulmonary exacerbations
We found that the oxidation of DCFH (DCF) was greater at 30, 45, and 60 days of exposure when compared to the group not exposed to cigarette smoke and in the 7 days of CS exposure group (Figure 1A)
CS induces pro-oxidants to increase oxidative stress in epithelial cells and other cells; autophagy is involved in this mechanism

Summary

Introduction

The human airway system is continuously exposed to numerous chemical toxicants, which lead to pulmonary exacerbations. Long-term exposure to cigarette smoke increases the risk of pulmonary-related diseases [1]. In response to irritant exposure, reactive oxygen species (ROS) activation, inflammatory response, and apoptosis occur, damaging the lung alveoli and leading to pulmonary pathologies, including chronic obstructive pulmonary disease (COPD)-emphysema. COPD-emphysema is a major leading cause of chronic morbidity and mortality worldwide and is projected to become the third leading cause of death in 2020 [2]. Alveolar emphysema is a primary cause of COPD and its early diagnosis may contribute to controlling this pathological condition. Recent evidence supports an important role for autophagy in the progression of COPD-emphysema [1,3,4]. Autophagy is an intracellular mechanism by which damaged cellular components and proteins are degraded and recycled by the cell itself as a defensive mechanism

Methods

Results

Conclusion