Oxidative stress is a potent link between hepatocyte damage and HSC activation in hepatic fibrosis

氧化应激在肝纤维化或细胞外基质沉积（ECM）的发展中起着致病作用。肝星状细胞（HSCs）在损伤肝脏中产生ECM成分。此外，NF-κB是炎症、感染和氧化应激反应中诱导多种基因的关键转录因子。诱导NF-κB活性的信号会导致i -κB -α蛋白的解离和随后的降解。然而，许多细胞都有自己独特的抗氧化应激酶防御系统，包括超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GPx）的产生，它们在保护细胞免受氧源性自由基和其他活性氧的侵害中起着关键作用。在本研究中，DMN模型的纤维化肝脏显示肝脏胶原蛋白和丙二醛（MDA）（脂质过氧化产物）水平升高，肝脏SOD和GPx水平降低。此外，我们的研究表明，培养的大鼠肝细胞对氧化应激反应强烈，i -κB -α降解和随后的NF-κB活化以及MDA和LDH分泌到培养基中具有时间依赖性。发现造血干细胞活化NF-κB并降解i -κB -α，添加MDA可增加α-SMA表达和胶原生成。这些发现表明，来自肝细胞氧化应激的旁分泌刺激至少部分通过i -κB -α降解和随后的NF-κB活化诱导HSC活化。

Oxidative stress has a causative role in the development of hepatic fibrosis, or the deposition of extracellular matrix (ECM). Hepatic stellate cells (HSCs) functions as the production of ECM components in the injured liver. In addition, NF-κB is a key transcription factor that induces multiple genes in response to inflammation, infections, and oxidative stress. Signals that induce NF-κB activity cause the dissociation and subsequent degradation of IκB-α protein. Whereas many cells have their own unique enzymatic defense systems against oxidative stress, including the production of superoxide dismutase (SOD) and glutathione peroxidase (GPx), which play a critical role in protecting the cell from oxygen-derived free radicals and other reactive oxygen species. In this study, the fibrotic livers of the DMN model showed the increased hepatic levels of collagen and malondialdehyde (MDA), a product of lipid peroxidation, and reduced hepatic levels of SOD and GPx In addition, our study demonstrated that cultured rat hepatocytes respond robustly to oxidative stress with a time-dependent increase in degradation of IκB-α and subsequent NF-κB activation as well as in secretion of MDA and LDH into the culture medium. HSCs were found to be activated NF-κB along with the IκB-α degradation and be increased α-SMA expression and collagen production by MDA supplementation. These findings suggest that paracrine stimuli derived from hepatocytes undergoing oxidative stress induce HSC activation, at least in part, through the degradation of IκB-α and subsequent NF-κB activation.