Hepatic fibrosis is caused by chronic inflammation and characterized as the excessive accumulation of extracellular matrix (ECM) by activated hepatic stellate cells (HSCs). Gasotransmitters like NO and CO are known to modulate inflammation and fibrosis, however, little is known about the role of the gasotransmitter hydrogen sulfide (H2S) in liver fibrogenesis and stellate cell activation. Endogenous H2S is produced by the enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CTH) and 3-mercaptopyruvate sulfur transferase (MPST) [1]. The aim of this study was to elucidate the role of endogenously produced and/or exogenously administered H2S on rat hepatic stellate cell activation and fibrogenesis. Primary rat HSCs were culture-activated for 7 days and treated with different H2S releasing donors (slow releasing donor GYY4137, fast releasing donor NaHS) or inhibitors of the H2S producing enzymes CTH and CBS (DL-PAG, AOAA). The main message of our study is that mRNA and protein expression level of H2S synthesizing enzymes are low in HSCs compared to hepatocytes and Kupffer cells. However, H2S promotes hepatic stellate cell activation. This conclusion is based on the fact that production of H2S and mRNA and protein expression of its producing enzyme CTH are increased during hepatic stellate cell activation. Furthermore, exogenous H2S increased HSC proliferation while inhibitors of endogenous H2S production reduce proliferation and fibrotic makers of HSCs. The effect of H2S on stellate cell activation correlated with increased cellular bioenergetics. Our results indicate that the H2S generation in hepatic stellate cells is a target for anti-fibrotic intervention and that systemic interventions with H2S should take into account cell-specific effects of H2S.

中文翻译：

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硫化氢通过增加细胞生物能来刺激肝星状细胞的活化。

肝纤维化是由慢性炎症引起的，其特征是活化的肝星状细胞（HSC）导致细胞外基质（ECM）过度积聚。众所周知，诸如NO和CO的气体递质可以调节炎症和纤维化，但是对于气体递质硫化氢（H2S）在肝纤维化和星状细胞激活中的作用了解甚少。内源性H2S是由胱硫醚β-合酶（CBS），胱硫醚γ-裂合酶（CTH）和3-巯基丙酮酸硫转移酶（MPST）产生的[1]。这项研究的目的是阐明内源性产生和/或外源性给予的硫化氢对大鼠肝星状细胞活化和纤维化的作用。将原代大鼠HSC培养激活7天，并用不同的H2S释放供体（缓释供体GYY4137，快速释放供体（NaHS）或产生H2S的酶CTH和CBS（DL-PAG，AOAA）的抑制剂。我们研究的主要信息是，与肝细胞和库普弗细胞相比，HSC中H2S合成酶的mRNA和蛋白质表达水平较低。但是，H2S促进肝星状细胞活化。该结论基于以下事实：在肝星状细胞激活过程中，H2S和mRNA的产生以及其产生的酶CTH的蛋白质表达增加。此外，外源性H2S增加了HSC的增殖，而内源性H2S产生的抑制剂则减少了HSC的增殖和纤维化生成物。H2S对星状细胞活化的影响与增加的细胞生物能有关。