Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
J Hepatol. 2012 Apr;56(4):893-9. doi: 10.1016/j.jhep.2011.11.013. Epub 2011 Dec 13.
BACKGROUND & AIMS: Liver fibrosis is associated with angiogenesis and leads to portal hypertension. Certain antibiotics reduce complications of liver failure in humans, however, the effects of antibiotics on the pathologic alterations of the disease are not fully understood. The aim of this study was to test whether the non-absorbable antibiotic rifaximin could attenuate fibrosis progression and portal hypertension in vivo, and explore potential mechanisms in vitro.
The effect of rifaximin on portal pressure, fibrosis, and angiogenesis was examined in wild type and Toll-like receptor 4 (TLR4) mutant mice after bile duct ligation (BDL). In vitro studies were carried out to evaluate the effect of the bacterial product and TLR agonist lipopolysaccharide (LPS) on paracrine interactions between hepatic stellate cells (HSC) and liver endothelial cells (LEC) that lead to fibrosis and portal hypertension.
Portal pressure, fibrosis, and angiogenesis were significantly lower in BDL mice receiving rifaximin compared to BDL mice receiving vehicle. Studies in TLR4 mutant mice confirmed that the effect of rifaximin was dependent on LPS/TLR4 pathway. Fibronectin (FN) was increased in the BDL liver and was reduced by rifaximin administration and thus, was explored further in vitro as a potential mediator of paracrine interactions of HSC and LEC. In vitro, LPS promoted FN production from HSC. Furthermore, HSC-derived FN promoted LEC migration and angiogenesis.
These studies expand our understanding of the relationship of intestinal microbiota with fibrosis development by identifying FN as a TLR4 dependent mediator of the matrix and vascular changes that characterize cirrhosis.
肝纤维化与血管生成有关，并导致门脉高压。某些抗生素可减少人类肝功能衰竭的并发症，但抗生素对疾病病理改变的影响尚未完全了解。本研究旨在检测不吸收抗生素利福昔明是否能减轻体内肝纤维化进展和门脉高压，并在体外探索潜在机制。
在胆管结扎（BDL）后，检测利福昔明对野生型和 Toll 样受体 4（TLR4）突变小鼠的门脉压、纤维化和血管生成的影响。体外研究评估细菌产物和 TLR 激动剂脂多糖（LPS）对导致纤维化和门脉高压的肝星状细胞（HSC）和肝内皮细胞（LEC）之间旁分泌相互作用的影响。
与接受载体的 BDL 小鼠相比，接受利福昔明的 BDL 小鼠的门脉压、纤维化和血管生成明显降低。在 TLR4 突变小鼠中的研究证实，利福昔明的作用依赖于 LPS/TLR4 途径。纤维连接蛋白（FN）在 BDL 肝脏中增加，利福昔明给药后减少，因此，在体外进一步研究作为 HSC 和 LEC 旁分泌相互作用的潜在介质。在体外，LPS 促进 HSC 产生 FN。此外，HSC 衍生的 FN 促进 LEC 迁移和血管生成。
这些研究通过鉴定 FN 作为 TLR4 依赖性基质和血管变化的介质，扩展了我们对肠道微生物群与纤维化发展之间关系的理解，这些变化是肝硬化的特征。
