Hydrogen Sulfide Inhibits Bronchial Epithelial Cell Epithelial Mesenchymal Transition Through Regulating Endoplasm Reticulum Stress

Abstract

Epithelial mesenchymal transition (EMT) is a contributing factor in remodeling events of chronic obstructive pulmonary disease (COPD). Hydrogen sulfide (H2S) has been implicated in the pathogenesis of COPD, but the effect of H2S in regulating EMT and the underlying mechanisms is not clear. In this study, we assessed endoplasmic reticulum (ER) stress markers, EMT markers and associated signal molecules in rat lungs, bronchial epithelial cells, and human peripheral lung tissues to investigate the effect of H2S in regulating EMT and the underlying mechanisms. We found that EMT and ER stress occurred in lung epithelial cells, especially in the bronchial epithelial cells of smokers and COPD patients. In cigarette smoke (CS)-exposed rats, intraperitoneal injection of NaHS significantly alleviated CS-induced lung tissue damage, small airway fibrosis, ER stress, and EMT, while intraperitoneal injection of propargylglycine (cystathionine-gamma-lyase inhibitor) aggravated these effects induced by CS. In the nicotine-exposed 16HBE cells, an appropriate concentration of H2S donor not only inhibited nicotine-induced ER stress, but also inhibited nicotine-induced enhancement of cell migration ability and EMT. ER stress nonspecific inhibitors taurine and 4-phenyl butyric acid also inhibited nicotine-induced enhancement of cell migration ability and EMT. Both H2S and inositol-requiring enzyme 1 (IRE1) activation inhibitor 4μ8C inhibited nicotine-induced activation of IRE1, Smad2/3 and EMT. These results suggest that H2S inhibits CS- or nicotine-induced ER stress and EMT in bronchial epithelial cells and alleviates CS-induced lung tissue damage and small airway fibrosis. The IRE1 signal pathway and Smad2/3 may be responsible for the inhibitory effect of H2S.

The role of sulfur compounds in chronic obstructive pulmonary disease

“…H 2 S upregulated sirtuin 1 expression, which improved mitochondrial function and reduced oxidative stress; thus, cell senescence induced by cigarette smoke was attenuated ( Guan et al, 2019 ). Hydrogen sulfide also inhibits EMT by regulating endoplasm reticulum stress (ERS) ( Lin et al, 2022 ). With ERS markers such as glucose-regulated protein-78 (GRP78), C/EBP homologous protein (CHOP), and caspase-12 were reduced in the COPD rat model that was established by passive smoke exposure and lipopolysaccharide irritation, pulmonary artery endothelial cell apoptosis was decreased ( Ding et al, 2018 ).…”

Endoplasmic Reticulum Stress in Chronic Obstructive Pulmonary Disease: Mechanisms and Future Perspectives

“…In addition to modulating the NLRP3 inflammasome, IRE1α can promote CS-induced airway inflammation by activating the NF-κB signaling pathway [ 129 , 130 ]. Furthermore, the activation of IRE1α played a crucial role in the nicotine-induced epithelial-mesenchymal transition and decreased cell migration capacity in human bronchial epithelial cells [ 152 ]. Epithelial-mesenchymal transition is a pivotal contributor to airway remodeling in COPD.…”

“…Scavenging the haem with salubrinal (eIF2α dephosphorylation inhibitor) suppressed ER stress, reduced elastase levels and activity, and attenuated the development of fibrosis and emphysema pathophysiological phenotypes in COPD. Hydrogen sulfide (H2S), as an endogenous modulator, attenuated smoke-induced apoptosis and epithelial-mesenchymal transition by inhibiting ER stress, thus hindering the progression of lung function decline and emphysema formation in rats [ 152 , 158 , 159 ]. Melatonin counteracts CS-induced inflammasome activation and apoptosis by inhibiting ER stress and mitochondrial dysfunction [ 129 , 160 ].…”

Identification of Genes Related to Endoplasmic Reticulum Stress (ERS) in Chronic Obstructive Pulmonary Disease (COPD) and Clinical Validation

“…Additionally, H 2 S, as an endogenous modulator, alleviated CS-induced rat lung cell apoptosis and Epithelial-Mesenchymal Transition (EMT) by suppressing endoplasmic enzyme stress, thereby impeding the progression of lung function decline and emphysema formation. [28][29][30] It has also been reported that melatonin inhibits ERS and mitochondrial dysfunction, counteracting CS-induced inflammasome activation and apoptosis. 31,32 The specific relationships between key genes and clinical indicators were also analyzed in the study.…”