Li Changyong, Jiang Xiangming, Yang Lin, Liu Xihong, Yue Shi, Li Liying
Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China.
Am J Pathol. 2009 Oct;175(4):1464-72. doi: 10.2353/ajpath.2009.090037. Epub 2009 Sep 3.
Bioactive sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) have been implicated in many critical cellular events, including inflammation, cancer, and angiogenesis. However, the role of S1P/S1PR signaling in the pathogenesis of liver fibrosis has not been well documented. In this study, we found that S1P levels and S1P(3) receptor expression in liver tissue were markedly up-regulated in a mouse model of cholestasis-induced liver fibrosis. In addition, the S1P(3) receptor was also expressed in green fluorescent protein transgenic bone marrow (BM)-derived cells found in the damaged liver of transplanted chimeric mice that underwent bile duct ligation. Silencing of S1P(3) expression significantly inhibited S1P-induced BM cell migration in vitro. Furthermore, a selective S1P(3) receptor antagonist, suramin, markedly reduced the number of BM-derived cells during cholestasis. Interestingly, suramin administration clearly ameliorated bile duct ligation-induced hepatic fibrosis, as demonstrated by attenuated deposition of collagen type I and III, reduced smooth muscle alpha-actin expression, and decreased total hydroxyproline content. In conclusion, our data suggest that S1P/S1P(3) signaling plays an important role in cholestasis-induced liver fibrosis through mediating the homing of BM cells. Modulation of S1PR activity may therefore represent a new antifibrotic strategy.
生物活性鞘氨醇-1-磷酸（S1P）及其受体（S1PRs）参与了许多关键的细胞活动，包括炎症、癌症和血管生成。然而，S1P/S1PR信号在肝纤维化发病机制中的作用尚未得到充分证明。在本研究中，我们发现胆汁淤积诱导的肝纤维化小鼠模型中，肝组织中的S1P水平和S1P(3)受体表达显著上调。此外，在接受胆管结扎的移植嵌合小鼠受损肝脏中发现的绿色荧光蛋白转基因骨髓（BM）来源的细胞中也表达了S1P(3)受体。沉默S1P(3)表达可显著抑制体外S1P诱导的BM细胞迁移。此外，选择性S1P(3)受体拮抗剂苏拉明可显著减少胆汁淤积期间BM来源细胞的数量。有趣的是，苏拉明给药明显改善了胆管结扎诱导的肝纤维化，表现为I型和III型胶原沉积减少、平滑肌α-肌动蛋白表达降低以及总羟脯氨酸含量减少。总之，我们的数据表明，S1P/S1P(3)信号通过介导BM细胞归巢在胆汁淤积诱导的肝纤维化中起重要作用。因此，调节S1PR活性可能代表一种新的抗纤维化策略。
