Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
Institution of Hepatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
Am J Physiol Gastrointest Liver Physiol. 2018 Sep 1;315(3):G374-G384. doi: 10.1152/ajpgi.00032.2018. Epub 2018 Apr 12.
Liver sinusoids serve as the first line of defense against extrahepatic stimuli from the intestinal tract. Hepatic stellate cells (HSCs) are pericytes residing in the perisinusoidal space that integrate cytokine-mediated inflammatory responses in the sinusoids and relay these signals to the liver parenchyma. Oxidative stress has been shown to promote inflammation during acute liver failure (ALF). Whether and how oxidative stress is involved in HSC inflammation during ALF remains unclear. Level of systemic oxidative stress is reflected by superoxide dismutase (SOD). Thus, ALF patients were recruited to investigate the correlation between plasma SOD levels and clinical features. Liver tissues were collected from chronic hepatitis patients by biopsy and from ALF patients who had undergone liver transplantation. SOD2 expression and HSCs activation were investigated by immunohistochemistry. Inflammation, mitophagy, and apoptosis were investigated by immunoblot analysis and flow cytometry in HSCs treated with lipopolysaccharide (LPS) and reactive oxygen species (ROS) donors. The plasma SOD level was significantly increased in patients with ALF compared with those with cirrhosis (444.4 ± 23.58 vs. 170.07 ± 3.52 U/ml, P < 0.01) and was positively correlated with the Model for End-Stage Liver Disease-Na score ( R = 0.4720, P < 0.01). In vivo observations revealed that SOD2 immunostaining was increased in ALF patients and mice models, and in vitro experiments demonstrated that LPS/ROS promoted inflammation via inhibiting mitophagy. Moreover, the regulation of inflammation was apoptosis independent in HSCs. LPS-induced increases in oxidative stress promote inflammation through inhibiting mitophagy in HSCs during the process of ALF, providing a novel strategy for the treatment of patients with ALF. NEW & NOTEWORTHY Here we demonstrate that the serum superoxide dismutase (SOD) level is significantly increased in patients with acute liver failure (ALF), and, correlated with the Model for End-Stage Liver Disease-Na score, SOD level dropped in the remission stage of ALF. We identify that, in liver tissue from ALF patients and mice models, manganese-dependent SOD was overexpressed, and show lipopolysaccharide/HO inhibits mitophagy via reactive oxygen species in hepatic stellate cells (HSCs). We show that inhibited mitophagy promotes inflammation in HSCs, whereas mitophagy inducer rescues HSCs from lipopolysaccharide-induced inflammation.
肝窦充当了抵御来自肠道的肝外刺激的第一道防线。肝星状细胞（HSCs）是驻留在窦周间隙中的周细胞，它们整合了细胞因子介导的窦内炎症反应，并将这些信号传递给肝实质。氧化应激已被证明会在急性肝衰竭（ALF）期间促进炎症。氧化应激是否以及如何参与 ALF 期间的 HSC 炎症仍不清楚。全身氧化应激水平反映在超氧化物歧化酶（SOD）中。因此，招募了 ALF 患者来研究血浆 SOD 水平与临床特征之间的相关性。通过活检从慢性肝炎患者和接受肝移植的 ALF 患者收集肝组织。通过免疫组化研究 SOD2 表达和 HSCs 激活。通过用脂多糖（LPS）和活性氧（ROS）供体处理 HSCs，进行免疫印迹分析和流式细胞术研究炎症、线粒体自噬和细胞凋亡。与肝硬化患者相比，ALF 患者的血浆 SOD 水平显著升高（444.4±23.58 与 170.07±3.52 U/ml，P<0.01），并且与终末期肝病模型-钠评分呈正相关（R=0.4720，P<0.01）。体内观察显示，ALF 患者和小鼠模型中 SOD2 免疫染色增加，体外实验表明 LPS/ROS 通过抑制线粒体自噬促进炎症。此外，在 HSCs 中，炎症的调节与细胞凋亡无关。在 ALF 过程中，LPS/ROS 通过抑制线粒体自噬促进 HSCs 中的氧化应激增加，为治疗 ALF 患者提供了一种新的策略。
在这里，我们证明急性肝衰竭（ALF）患者的血清超氧化物歧化酶（SOD）水平显著升高，与终末期肝病模型-钠评分相关，ALF 的缓解期 SOD 水平下降。我们发现，在 ALF 患者和小鼠模型的肝组织中，锰依赖性 SOD 过度表达，并表明脂多糖/HO 通过活性氧在肝星状细胞（HSCs）中抑制线粒体自噬。我们表明，抑制线粒体自噬可促进 HSCs 中的炎症，而线粒体自噬诱导剂可挽救 LPS 诱导的 HSCs 炎症。
