Max-Planck Institute for Biochemistry, Martinsried, Germany; Institute for Immunology, University of Heidelberg, Heidelberg, Germany.
Department of Medicine I, University of Heidelberg at Mannheim, Mannheim, Germany.
J Hepatol. 2015 Mar;62(3):625-33. doi: 10.1016/j.jhep.2014.06.010. Epub 2014 Jun 16.
BACKGROUND & AIMS: Common pathogenic steps in liver fibrosis are inflammation and accumulation of extracellular matrix proteins including collagen, which lead to disruption of tissue microarchitecture and liver dysfunction. Adequate fibronectin fibril formation is required for collagen matrix deposition in several cell types in vitro. We therefore hypothesized that preventing fibronectin fibril assembly will result in decreased collagen matrix accumulation, and hence diminish liver injury associated with fibrosis.
In vitro studies on hepatic stellate cells and in vivo studies in mice were performed.
In vitro studies on hepatic stellate cells confirmed that a fibronectin assembly inhibitor, pUR4 diminishes the amount of both fibronectin and collagen, accumulating in the extracellular matrix, without affecting their production. Induction of fibrosis using CCl4 or DMN was therefore combined with pUR4-treatment. pUR4 normalized the amount of fibrotic tissue that accumulated with injury, and improved liver function. Specifically, pUR4-treatment decreased collagen accumulation, without changing its mRNA expression. Most interestingly, we did not detect any changes in Kupffer cell numbers (F4/80+) or α-smooth muscle actin expressing hepatic stellate cell numbers. Further, there was no impact on TGF-β or TNF-α. Thus, in line with the in vitro findings, decreased fibrosis is due to inhibition of matrix accumulation and not a direct effect on these cells.
In summary, a peptide that blocks fibronectin deposition results in decreased collagen accumulation and improved liver function during liver fibrogenesis. Thus, fibronectin matrix modulation offers a therapeutic benefit in preclinical models of liver fibrosis.
肝纤维化的常见致病步骤是炎症和细胞外基质蛋白（包括胶原）的积累，这导致组织微结构的破坏和肝功能障碍。在几种体外细胞类型中，纤维连接蛋白纤维的适当形成是胶原基质沉积所必需的。因此，我们假设阻止纤维连接蛋白纤维组装将导致胶原基质积累减少，从而减轻与纤维化相关的肝损伤。
进行了肝星状细胞的体外研究和小鼠的体内研究。
肝星状细胞的体外研究证实，纤维连接蛋白组装抑制剂 pUR4 减少了细胞外基质中积累的纤维连接蛋白和胶原的量，而不影响其产生。因此，用 CCl4 或 DMN 诱导纤维化，并联合 pUR4 治疗。pUR4 使与损伤相关的纤维化组织量正常化，并改善肝功能。具体而言，pUR4 治疗减少了胶原的积累，而不改变其 mRNA 表达。最有趣的是，我们没有检测到库普弗细胞（F4/80+）数量或表达α-平滑肌肌动蛋白的肝星状细胞数量的任何变化。此外，对 TGF-β 或 TNF-α 没有影响。因此，与体外研究结果一致，减少纤维化是由于基质积累的抑制，而不是对这些细胞的直接影响。
总之，阻断纤维连接蛋白沉积的肽可减少胶原积累并改善肝纤维化过程中的肝功能。因此，纤维连接蛋白基质调节在肝纤维化的临床前模型中提供了治疗益处。
