Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Uchinada, Ishikawa 920-0293, Japan.
Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
Int J Mol Sci. 2018 Aug 24;19(9):2509. doi: 10.3390/ijms19092509.
Accumulating evidence indicates that oxidative stress plays a critical role in initiating the progression of inflammatory and fibrotic liver diseases, including cholestatic hepatitis. Peroxiredoxin 4 (PRDX4) is a secretory antioxidase that protects against oxidative damage by scavenging reactive oxygen species (ROS) in both the intracellular compartments and extracellular space. In this study, we examined the in vivo net effects of PRDX4 overexpression in a murine model of cholestasis. To induce cholestatic liver injury, we subjected C57BL/6J wild-type (WT) or human PRDX4 (hPRDX4) transgenic (Tg) mice to sham or bile duct ligation (BDL) surgery for seven days. Our results showed that the liver necrosis area was significantly suppressed in Tg BDL mice with a reduction in the severity of liver injuries. Furthermore, PRDX4 overexpression markedly reduced local and systemic oxidative stress generated by BDL. In addition, suppression of inflammatory cell infiltration, reduced proliferation of hepatocytes and intrahepatic bile ducts, and less fibrosis were also found in the liver of Tg BDL mice, along with a reduced mortality rate after BDL surgery. Interestingly, the composition of the hepatic bile acids (BAs) was more beneficial for Tg BDL mice than for WT BDL mice, suggesting that PRDX4 overexpression may affect BA metabolism during cholestasis. These features indicate that PRDX4 plays an important role in protecting against liver injury following BDL and might be a promising therapeutic modality for cholestatic diseases.
越来越多的证据表明，氧化应激在启动炎症和纤维化性肝病（包括胆汁淤积性肝炎）的进展中起着关键作用。过氧化物酶 4（PRDX4）是一种分泌型抗氧化酶，可通过清除细胞内区室和细胞外空间中的活性氧（ROS）来防止氧化损伤。在这项研究中，我们在胆汁淤积的小鼠模型中检查了 PRDX4 过表达的体内净效应。为了诱导胆汁淤积性肝损伤，我们使 C57BL/6J 野生型（WT）或人 PRDX4（hPRDX4）转基因（Tg）小鼠接受假手术或胆管结扎（BDL）手术 7 天。我们的结果表明，TgBDL 小鼠的肝坏死面积明显受到抑制，肝损伤的严重程度降低。此外，PRDX4 过表达显著降低了 BDL 引起的局部和全身氧化应激。此外，在 TgBDL 小鼠的肝脏中还发现了炎症细胞浸润的抑制、肝细胞和肝内胆管增殖的减少以及纤维化的减少，并且 BDL 手术后的死亡率降低。有趣的是，肝胆汁酸（BAs）的组成对 TgBDL 小鼠比 WTBDL 小鼠更有利，表明 PRDX4 过表达可能会影响胆汁淤积期间的 BA 代谢。这些特征表明，PRDX4 在防止 BDL 后肝损伤中起着重要作用，并且可能是胆汁淤积性疾病的有前途的治疗方式。
