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

氧化应激是肝纤维化过程中肝细胞损伤和 HSC 激活之间的重要联系

基本信息

批准号：
11670509
负责人：
SHIMIZU Ichiro
金额：
$ 2.24万
依托单位：
Tokushima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670509/
关键词：
Oxidative stress Hepatic fibrosis Lipid peroxidation Hepatic stellate cell Hepatocyte SOD MDA Glutathione peroxidase

项目摘要

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.

氧化应激在肝纤维化的发生、发展和细胞外基质（ECM）的沉积中起重要作用。肝星状细胞（HSC）在受损的肝脏中作为ECM成分的产生而发挥作用。此外，NF-κB是一种关键的转录因子，可诱导多种基因对炎症、感染和氧化应激做出反应。诱导NF-κB活性的信号导致IκB-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酶防御系统来对抗氧化应激，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方面发挥着关键作用。在这项研究中，DMN模型的纤维化肝脏显示胶原蛋白和脂质过氧化产物丙二醛（MDA）的肝脏水平增加，以及SOD和GPx的肝脏水平降低。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，IκB-α和随后的NF-κ B-α降解呈时间依赖性增加。κB活化以及MDA和LDH分泌到培养基中。MDA可激活HSC中的NF-κB沿着促进IκB-α降解，增加α-SMA表达和胶原合成。这些结果表明，来自肝细胞的旁分泌刺激诱导HSC活化，至少部分是通过降解IκB-α和随后的NF-κB活化。