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(ECM)沉积中起致病作用。肝星状细胞(HSCs)在损伤的肝脏中作为ECM成分的产物。此外，NF-κB是一种关键的转录因子，可诱导多个基因对炎症、感染和氧化应激做出反应。诱导核因子-κB活性的信号导致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酶防御系统来抵御氧化应激，包括产生超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GPX)，它们在保护细胞免受氧自由基和其他活性氧物种的伤害方面发挥着关键作用。在本研究中，DMN模型的肝纤维化表现为肝脏胶原和脂质过氧化产物丙二醛水平升高，肝脏超氧化物歧化酶和谷丙转氨酶水平降低。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的降解和随后的NF-κB的活化以及培养上清液中丙二醛和乳酸脱氢酶的分泌呈时间依赖性增加。补充丙二醛可激活NF-κB并降解I-κB-α，增加α-SMA的表达和胶原的产生。这些发现表明，氧化应激肝细胞产生的旁分泌刺激至少部分地通过I-κB-α的降解和随后的NF-κB激活来诱导肝星状细胞的激活。

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.