Inhibition of RAGE Attenuates Cigarette Smoke-Induced Lung Epithelial Cell Damage via RAGE-Mediated Nrf2/DAMP Signaling.

Hanbyeol Lee,Seok-Ho Hong,Se-Ran Yang,Jooyeon Lee,Irfan Rahman

doi:10.3389/fphar.2018.00684

Abstract

The oxidative stress and cellular apoptosis by environmental factor including cigarette smoke induces alveolar airway remodeling leading to chronic obstructive pulmonary disease (COPD). Recently, the receptor for advanced glycan end products (RAGE) which is highly expressed in alveolar epithelium is emerging as a biomarker for COPD susceptibility or progression. However, it still remains unknown how RAGE plays a role in cigarette smoke extract (CSE)-exposed human alveolar type II epithelial cell line. Therefore, we determined the efficacy of RAGE-specific antagonist FPS-ZM1 in response to CSE-induced lung epithelial cells. CSE induced the elevated generation of RONS and release of pro-inflammatory cytokines, and impaired the cellular antioxidant defense system. Further, CSE induced the alteration of RAGE distribution via the activation of redox-sensitive DAMP (Damage-associated molecular patterns) signaling through Nrf2 in cells. Although pre-treatment with SB202190 (p38 inhibitor) or SP600125 (JNK inhibitor) failed to recover the alteration of RAGE distribution, treatment of FPS-ZM1 significantly exhibited anti-inflammatory and anti-oxidative/nitrosative effects, also inhibited the activation of redox-sensitive DAMP signaling through Nrf2 (nuclear factor erythroid 2-related factor 2) migration in the presence of CSE. Taken together, our data demonstrate that RAGE and Nrf2 play a pivotal role in maintenance of alveolar epithelial integrity.

Highlights

Cigarette smoke (CS) is a major contributor in reproductive and developmental effects (Boucherat et al, 2016), aging (Sundar et al, 2015), cancer (Stampfli and Anderson, 2009), cardiovascular disease (Morris et al, 2015; Lahousse et al, 2016), and pulmonary diseases including chronic obstructive pulmonary disease (COPD)/emphysema and idiopathic pulmonary fibrosis
When these the expression of receptor for advanced glycation end products (RAGE) isoform and their signaling become aberrantly regulated either by persisting stimuli or by impeded resolution, they turn out to be highly destructive for the surrounding epithelium and may causes severe damage and epithelium break down as observed in chronic obstructive disease/emphysema In our recent study, we showed upregulation of cellular expression of RAGE, initiating inflammatory response, and downregulation of soluble RAGE, acting as a ‘decoy’ in protein, serum and bronchoalveolar lavage fluid in the elastase-induced experimental COPD mice and in cell lysate in CS extract (CSE)-induced mouse alveolar type II epithelial cells as well as in the serum and protein of COPD patients (Lee H. et al, 2017)
As unrestrained high reactive oxygen and nitrogen species (RONS) concentrations with prolonged oxidative stress are responsible for this vicious sequence of events, we determined the effect of FPS-ZM1 in CSE-induced human alveolar epithelial type II cell line A549

Summary

Introduction

Cigarette smoke (CS) is a major contributor in reproductive and developmental effects (Boucherat et al, 2016), aging (Sundar et al, 2015), cancer (Stampfli and Anderson, 2009), cardiovascular disease (Morris et al, 2015; Lahousse et al, 2016), and pulmonary diseases including chronic obstructive pulmonary disease (COPD)/emphysema and idiopathic pulmonary fibrosis. The truncated circulating soluble form of RAGE undergoing RNA splicing (esRAGE) or proteolysis (sRAGE) lacks the transmembrane domain of full-length RAGE, released into the extracellular space and suppressing the activation of full-length RAGE and intracellular danger signals known as damage-associated molecular patterns (DAMPs) signaling When these the expression of RAGE isoform and their signaling become aberrantly regulated either by persisting stimuli or by impeded resolution, they turn out to be highly destructive for the surrounding epithelium and may causes severe damage and epithelium break down as observed in chronic obstructive disease/emphysema In our recent study, we showed upregulation of cellular expression of RAGE, initiating inflammatory response, and downregulation of soluble RAGE, acting as a ‘decoy’ in protein, serum and bronchoalveolar lavage fluid in the elastase-induced experimental COPD mice and in cell lysate in CSE-induced mouse alveolar type II epithelial cells as well as in the serum and protein of COPD patients (Lee H. et al, 2017). This results make it a basis for future study for RAGE blockade-based therapies in airways disease

Objectives

Methods

Results

Conclusion