Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niao-Sung District, Kaohsiung 833, Taiwan, ROC.
Peptides. 2012 Jun;35(2):212-7. doi: 10.1016/j.peptides.2012.03.032. Epub 2012 Apr 5.
Obstructive jaundice (OJ) increases the risk of liver injury and sepsis, leading to increased mortality. Cholestatic liver injury is associated with a downregulation of hepcidin expression levels. In fact, hepcidin has an important antimicrobial effect, especially against Escherichia coli. It is unknown whether supplementing recombinant hepcidin is effective in alleviating cholestasis-induced liver injury and mortality in mice with superimposed sepsis. A mouse model of cholestasis was developed using extrahepatic bile duct ligation for 3 days. In addition, sepsis due to E. coli 0111:B4 lipopolysaccharide (LPS) was induced in the model. The serum levels of total bilirubin, AST, ALT, and LDH and the mRNA levels of IL-1β, TNF-α, and MCP-1 in the liver were significantly higher in the OJ mice receiving LPS than in the sham-operated mice receiving LPS. Compared to the OJ mice receiving LPS, the hepcidin-pretreated OJ mice receiving LPS showed a significant decrease in the above mentioned parameters, as well as a reversal in the downregulation of LC3B-II and upregulation of cleaved caspase-3; this, in turn, led to significantly decreased lethality in 24h. In conclusion, these results indicate that hepcidin pretreatment significantly reduced hepatic proinflammatory cytokine expression and liver injury, leading to reduced early lethality in OJ mice receiving LPS. Enhanced autophagy and reduced apoptosis may account for the protective effects of hepcidin.
梗阻性黄疸（OJ）增加了肝损伤和脓毒症的风险，导致死亡率增加。胆汁淤积性肝损伤与铁调素表达水平下调有关。事实上，铁调素有重要的抗菌作用，特别是针对大肠杆菌。目前尚不清楚在合并脓毒症的 OJ 小鼠中补充重组铁调素是否能有效缓解胆汁淤积性肝损伤和死亡率。通过对胆总管结扎 3 天建立了 OJ 小鼠模型。此外，在模型中诱导了由大肠杆菌 0111:B4 脂多糖（LPS）引起的脓毒症。与接受 LPS 的假手术组相比，接受 LPS 的 OJ 小鼠的血清总胆红素、AST、ALT 和 LDH 水平以及肝内 IL-1β、TNF-α 和 MCP-1 的 mRNA 水平明显升高。与接受 LPS 的 OJ 小鼠相比，接受 LPS 的铁调素预处理 OJ 小鼠上述参数明显降低，LC3B-II 下调和 cleaved caspase-3 上调得到逆转；这反过来导致 LPS 后 24 小时的死亡率显著降低。总之，这些结果表明，铁调素预处理可显著降低肝内促炎细胞因子的表达和肝损伤，从而降低接受 LPS 的 OJ 小鼠的早期死亡率。增强自噬和减少细胞凋亡可能是铁调素的保护作用的原因。
