Hydrogen Sulfide Inhibits Cigarette Smoke-Induced Endoplasmic Reticulum Stress and Apoptosis in Bronchial Epithelial Cells

Abstract

Background: Apoptosis of lung structural cells contributes to the process of lung damage and remodeling in chronic obstructive pulmonary disease (COPD). Our previous studies demonstrated that exogenous hydrogen sulfide (H2S) can reduce the lung tissue pathology score, anti-inflammation and anti-oxidation effects in COPD, but the effect of H2S in regulating cigarette smoke (CS) induced bronchial epithelial cell apoptosis and the underlying mechanisms are not clear.Objectives: To investigate the effect of H2S on CS induced endoplasmic reticulum stress (ERS) and bronchial epithelial cell apoptosis.Methods: Male Sprague–Dawley rats randomly divided into four groups for treatment: control, CS, NaHS + CS, and propargylglycine (PPG) + CS. The rats in the CS group were exposed to CS generated from 20 commercial unfiltered cigarettes for 4 h/day, 7 days/week for 4 months. Since the beginning of the third month, freshly prepared NaHS (14 μmol/kg) and PPG (37.5 mg/kg) were intraperitoneally administered 30 min before CS-exposure in the NaHS and PPG groups. 16HBE cells were pretreated with Taurine (10 mM), 5 mmol/L 4-phenylbutyric acid (4-PBA) or NaHS (100, 200, and 400 μM) for 30 min, and then cells were exposed to 40 μmol/L nicotine for 72 h. ERS markers (GRP94, GRP78) and ERS-mediated apoptosis markers 4-C/EBP homologous protein (CHOP), caspase-3 and caspase-12 were assessed in rat lung tissues and human bronchial epithelial cells. The apoptotic bronchial epithelial cells were detected by Hoechst staining in vitro and TUNEL staining in vivo.Results: In CS exposed rats, peritoneal injection of NaHS significantly inhibited CS induced overexpression ERS-mediated apoptosis markers and upregulation of apoptotic rate in rat lungs, and inhibiting the endogenous H2S production by peritoneal injection of PPG exacerbated these effects. In the nicotine-exposed bronchial epithelial cells, appropriate concentration of NaHS and ERS inhibitors taurine and 4-PBA inhibited nicotine-induced upregulation of apoptotic rate and overexpression of ERS-mediated apoptosis markers.Conclusion: H2S inhibited lung tissue damage by attenuating CS induced ERS in rat lung and exogenous H2S attenuated nicotine induced ERS-mediated apoptosis in bronchial epithelial cells.

Hydrogen Sulfide Attenuates Particulate Matter-Induced Emphysema and Airway Inflammation Through Nrf2-Dependent Manner

“…*p< 0.05, **p < 0.01, ***p < 0.001 between groups. PM 2.5 , fine particulate matter; Nrf2, nuclear factor erythroid 2 related factor 2. against cigarette smoke or ozone induced-COPD/emphysema, which further demonstrated that H 2 S was endogenous protection system in vivo and in vitro (Li F. et al, 2016;Lin et al, 2017). Though our study demonstrated that PM impaired endogenous H 2 S generation to cause lung damage, however, how PM decreased endogenous CTH expression level needs further study.…”

“…Our previous study showed that H 2 S was able to inhibit cigarette smoke-induced apoptosis in rat lung and bronchial epithelial cells (Lin et al, 2017). Its also reported that the activation of Nrf2 by bixin protected against PM 2.5 -induced lung injury by alleviating oxidative stress, increasing proliferation and migration, decreasing apoptosis (Zhang H. et al, 2018;Liu et al, 2019).…”

“…We previous reported that hydrogen sulfide (H 2 S), a novel gaseous signal molecule, also severed as defense system in lung, was impaired in COPD patients (Chen et al, 2005;Sun et al, 2015). And H 2 S exerted significant protect role in defending against cigarette smoke or ozone exposure caused COPD/ emphysema via the anti-oxidative stress, anti-apoptosis, antiendoplasmic reticulum stress, anti-inflammatory function of H 2 S (Han et al, 2011;Li F. et al, 2016;Lin et al, 2017). Recent studies demonstrated that H 2 S inhibited reactive oxygen species (ROS) generation, NLRP3 inflammasome and apoptosis to improve endothelial dysfunction in spontaneously hypertensive rats, attenuate high glucose-induced human retinal pigment epithelial cell inflammation and attenuate pathogenesis of ozone-induced mice lung inflammation and emphysema (Li F. et al, 2016;Li et al, 2019;Wang et al, 2019).…”

Hydrogen sulfide, oxygen, and calcium regulation in developing human airway smooth muscle

“…In mice, absence of CSE expression promotes AHR. 29 Exogenous administration of H 2 S has been demonstrated as protective in ventilator-induced lung injury, 68,69 acute lung injury, [70][71][72][73][74] hypoxia/hyperoxia environments, [74][75][76] and during acute viral illnesses. [77][78][79] Compared to these data, there is currently no information on H 2 S in the developing bronchial airways per se.…”

Hydrogen Sulfide Plays an Important Protective Role through Influencing Endoplasmic Reticulum Stress in Diseases

“…Cigarette smoke (CS) induces ERS and ERS-mediated apoptosis and suppresses the production of endogenous H2S to lead COPD, which is reversed by exogenous H 2 S [83]. Intraperitoneal injection of endogenous H 2 S inhibitor in rat model of passive inhalation of CS aggravates these effects caused by CS; however, the ERS inhibitor suppresses CS-induced effects, which suggests that H 2 S may inhibit CS-induced bronchial epithelial cell apoptosis through suppressing ERS [84]. Artery endothelial dysfunction induced by apoptosis of arterial endothelial cells is associated with the severity of COPD [85].…”