Section of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA.
Hepatology. 2012 May;55(5):1518-28. doi: 10.1002/hep.25500. Epub 2012 Mar 18.
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 lipopolysaccharide (LPS)-Toll-like receptor 4 (TLR4) signaling dependent Kupffer cell (KC) 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 (PN7d/DSS) and 28 (PN28d/DSS) days. Purified KCs were probed for transcription of proinflammatory cytokines. PN7d/DSS mice showed increased intestinal permeability and elevated portal vein LPS levels, evidence of hepatocyte injury and cholestasis (serum aspartate aminotransferase, alanine aminotransferase, bile acids, total bilirubin), and increased KC expression of interleukin-6 (Il6), tumor necrosis factor α (Tnfα), and transforming growth factor β (Tgfβ). Markers of liver injury remained elevated in PN28d/DSS mice associated with lobular inflammation, hepatocyte apoptosis, peliosis, and KC hypertrophy and hyperplasia. PN infusion without DSS pretreatment or DSS pretreatment alone did not result in liver injury or KC activation, even though portal vein LPS levels were elevated. Suppression of the intestinal microbiota with broad spectrum antibiotics or ablation of TLR4 signaling in Tlr4 mutant mice resulted in significantly reduced KC activation and markedly attenuated liver injury in PN7d/DSS mice.
These data suggest that intestinal-derived LPS activates KC through TLR4 signaling in early stages of PNALI.
依赖于肠外营养（PN）的患有肠衰竭的婴儿可能会发展为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，肠损伤导致肠通透性增加，再加上 PN 的给予，会促进脂多糖（LPS）-Toll 样受体 4（TLR4）信号依赖性枯否细胞（KC）激活，这是 PNALI 发病机制中的早期事件。我们建立了一种小鼠模型，通过口服给予硫酸葡聚糖钠（DSS）连续治疗 4 天来诱导肠损伤和通透性增加，然后通过中心静脉导管连续输注大豆脂质基 PN 溶液 7（PN7d/DSS）和 28（PN28d/DSS）天。检测纯化的 KC 中促炎细胞因子的转录。PN7d/DSS 小鼠表现出增加的肠通透性和门静脉 LPS 水平升高，提示肝细胞损伤和胆汁淤积（血清天冬氨酸转氨酶、丙氨酸转氨酶、胆汁酸、总胆红素），以及 KC 中白细胞介素-6（Il6）、肿瘤坏死因子 α（Tnfα）和转化生长因子 β（Tgfβ）表达增加。PN28d/DSS 小鼠的肝损伤标志物仍升高，伴有小叶炎症、肝细胞凋亡、肝血窦扩张和 KC 肥大和增生。没有 DSS 预处理的 PN 输注或单独 DSS 预处理不会导致肝损伤或 KC 激活，即使门静脉 LPS 水平升高。广谱抗生素抑制肠道微生物群或 Tlr4 突变小鼠 TLR4 信号的消融导致 PN7d/DSS 小鼠 KC 激活明显减少，肝损伤明显减轻。
这些数据表明，PNALI 的早期阶段，肠道来源的 LPS 通过 TLR4 信号激活 KC。
