Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury.
Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury.
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DOI：
10.1002/hep.25500
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发表时间：
2012-05
期刊：
影响因子：
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通讯作者：
Sokol RJ
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文献类型：
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作者：
El Kasmi KC;Anderson AL;Devereaux MW;Fillon SA;Harris JK;Lovell MA;Finegold MJ;Sokol RJ
肠外营养（PN）依赖性肠衰竭婴儿可能发生胆汁淤积性肝损伤和肝硬化（PN相关肝损伤：PNALI）。PNALI的发病机制仍不完全清楚。我们假设肠通透性增加的肠损伤与PN联合给药促进LPS-TLR 4信号传导依赖性枯否细胞活化作为PNALI发病机制的早期事件。我们开发了一种小鼠模型，在该模型中，通过口服葡聚糖硫酸钠（DSS）4天，然后通过中心静脉导管连续输注基于大豆脂质的PN溶液7（PN/DSS 7 d）和28（PN/DSS 28 d）天，诱导肠损伤和通透性增加。通过血清AST、ALT、胆汁酸、总胆红素和组织学评价肝损伤和胆汁淤积。探测纯化的库普弗细胞的促炎细胞因子的转录。PN/DSS 7 d小鼠门静脉LPS水平升高，肝细胞损伤和胆汁淤积的证据，以及IL 6、TNFα和TGFβ的枯否细胞表达增加。在PN/DSS 28 d小鼠中，肝损伤的血清学标志物仍然升高，与局灶性炎症、肝细胞凋亡、紫癜和枯否细胞肥大和增生相关。无DSS预处理或仅DSS预处理的PN输注未导致肝损伤或枯否细胞活化。在TLR 4突变小鼠中用广谱抗生素抑制肠道微生物群或消除TLR 4信号传导导致PN/DSS 7 d小鼠中库普弗细胞活化显著降低并显著减轻肝损伤。这些数据表明，在PNALI的早期阶段，脑源性LPS通过TLR 4信号传导激活枯否细胞。
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. 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/DSS7d) and 28 (PN/DSS28d) 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. PN/DSS7d mice showed elevated portal vein LPS levels, evidence of hepatocyte injury and cholestasis, and increased Kupffer cell expression of IL6, TNFα, and TGFβ. Serological markers of liver injury remained elevated in PN/DSS28d 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/DSS7d mice. These data suggest that intestinal-derived LPS activates Kupffer cells through TLR4 signaling in early stages of PNALI.