Protective effects of hydrogen sulfide on oxidative stress and fibrosis in hepatic stellate cells

Abstract

In hepatic fibrosis, hepatic stellate cells (HSCs) are activated and change into myofibroblast-like cells which are characterized by increased proliferation and extracellular matrix (ECM) synthesis. In this study, we investigated the regulatory effects of hydrogen sulfide (H2S) on hepatic fibrosis. We detected the proliferation, cell cycle progression, apoptosis, intracellular reactive oxygen species (ROS) and free calcium levels in ferric nitrilotriacetate (Fe-NTA)-activated HSCs treated with sodium hydrogen sulphide (NaHS), an H2S-releasing molecule. We also evaluated the effects of NaHS on fibrosis and ECM synthesis in rats with hepatic fibrosis induced by carbon tetrachloride (CCl4). MTT assay revealed that NaHS (500 µmol/l) suppressed the Fe-NTA-induced proliferation of HSC-T6 cells in a dose-dependent manner. NaHS induced G1 phase cell cycle arrest and apoptosis in the Fe-NTA-treated HSC-T6 cells. Furthermore, in the Fe-NTA-treated HSC-T6 cells, NaHS reduced intracellular levels of ROS at 1, 3 and 6 h and reduced intracellular free calcium levels at 3 and 6 h. H2S administration attenuated hepatic fibrosis and collagen Ⅰ protein expression in the rats with CCl4-induced hepatic fibrosis. In conclusion, exogenous H2S inhibits proliferation and induces cell cycle arrest and apoptosis in activated HSCs and attenuates CCl4-induced hepatic fibrosis and ECM expression.

Sodium thiosulfate attenuates angiotensin II-induced hypertension, proteinuria and renal damage11These authors contributed equally to this manuscript.

“…The attenuation of fibrosis by H2S treatment is in concordance with literature showing decreased fibrosis in various organs following H2S exposure [46,[50][51][52]. STS outperformed NaHS with regard to decreased αSMA levels, which might be related to the lower level of interstitial macrophages in the former.…”

Diallyl Trisulfide Suppresses Oxidative Stress‐Induced Activation of Hepatic Stellate Cells through Production of Hydrogen Sulfide

“…Consistent with our data, recent investigations showed that sodium hydrosulfide, a well-known inorganic H 2 S-releasing molecule, suppressed proliferation and induced G1 phase cell cycle arrest in HSCs [17] and attenuated collagen expression in rats with CCl 4 -induced hepatic fibrosis [18]. These findings collectively suggested H 2 S as a signaling molecule regulating the pathophysiology of HSCs.…”

The CBS/CSE system: a potential therapeutic target in NAFLD?

“…Activation of these cells is induced by a variety of cytotoxic stimuli including oxidative stress and mitogenic and pro-inflammatory cytokines (Mallat and Lotersztajn 2013). In one study, exogenous H 2 S effectively inhibited the proliferation of stimulated rat hepatic stellate cells by reducing oxidative stress and increasing apoptosis in these cells (Fan et al 2013b). Clearance of activated hepatic stellate cells is essential for the regression of fibrosis (Mallat and Lotersztajn 2013).…”