摘要：背景：婴儿肠衰竭肠外营养（PN）的依赖可能发展为胆汁淤积性肝损伤和肝硬化。（肠外营养相关性肝损伤）。PNALI的发病机制仍不完全清楚。方法：我们假设，肠道损伤和增加肠道通透性与肠外营养给药相结合，LPS-TLR4的信号依赖的枯否细胞活化为促进PNALI发病机制的早期事件。我们制定了一个小鼠模型诱导肠道损伤和增加肠道通透性，方法是口服4天葡聚糖硫酸钠（DSS），随后通过中央静脉导管持续输注大豆脂质，分别7天（PN/DSS 7d）和28天（PN/DSS 28d）。以血清AST、ALT、胆汁酸、总胆红素和组织学类型来评估肝损伤和胆汁淤积，探讨纯化的枯否细胞促炎性细胞因子的转录。结果：PN/DSS7d 小鼠门静脉内毒素水平升高，发现肝细胞损伤和胆汁淤积，肝细胞表达IL-6，TNFα，TGFβ增加。PN/DSS28d小鼠肝损伤的血清标志物仍持续升高，合并局灶性炎症，肝细胞凋亡，紫癜，枯否细胞肥大和增生。PN没有DSS前处理组和只有DSS的前处理组并不导致肝损伤或枯否细胞活化。广谱抗生素抑制肠道菌群或TLR4突变小鼠TLR4的信号消融，显著减少枯否细胞活化，明显减弱PN/DSS 7d小鼠肝损伤。结论：这些资料表明，肠源性内毒素通过TLR4信号在PNALI早期激活枯否氏细胞。
吉林大学第一医院肝胆胰内科 何芳慧 摘译
本文首次发表于[Hepatology.2011 Nov 26.]
Toll like receptor 4 dependent kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition.
Abstract：
Background：Infants with intestinal failure who are parenteral nutrition (PN)-dependent may develop cholestatic liver injury and cirrhosis (PN-associated liver injury:PNALI).The pathogenesis of PNALI remains incompletely understood.
Methods ：We hypothesized that intestinal injury with increased intestinal permeability combined with administration of PN promotes LPS-TLR4 signaling dependent Kupffer cell activation as an early event in the pathogenesis of PNALI. We developed a mouse model in which intestinal injury and increased permeability were induced by oral treatment for 4 days with dextran sulphate sodium(DSS) followed by continuous infusion of soy lipid-based PN solution through a central venous catheter for 7 (PN/DSS 7d) and 28 (PN/DSS 28d) days. Liver injury and cholestasis were evaluated by serum AST, ALT, bile acids, total bilirubin, and by histology. Purified Kupffer cells were probed for transcription of pro-inflammatory cytokines.
Results：PN/DSS 7d mice showed elevated portal vein LPS levels, evidence of hepatocyte injury and cholestasis, and increased Kupffer cell expression of IL-6, TNF-α, and TGF-β. Serological markers of liver injury remained elevated in PN/DSS 28d mice associated with focal inflammation, hepatocyte apoptosis, peliosis, and Kupffer cell hypertrophy and hyperplasia.PN infusion without DSS pre-treatment or DSS pre-treatment alone did not result in liver injury or Kupffer cell activation. Suppression of the intestinal microbiota with broad spectrum antibiotics or ablation of TLR4 signaling in TLR4 mutant mice resulted in significantly reduced Kupffer cell activation and markedly attenuated liver injury in PN/DSS 7d mice.
Conclusion：These data sugges tthat intestinal-derived LPS activates Kupffer cells through TLR4 signaling in early stages of PNALI.
