Department of Mental Health and Preventive Medicine, Section of Infectious Diseases, University of Campania "L. Vanvitelli", Naples, Italy.
Department of Mental Health and Preventive Medicine, Section of Human Anatomy, University of Campania "L. Vanvitelli", Naples, Italy.
J Cell Physiol. 2018 Aug;233(8):6224-6231. doi: 10.1002/jcp.26485. Epub 2018 Mar 12.
After an acute liver damage, tissue regeneration repairs lesions with degradation of deposed fibrotic material, while mechanisms of tissue restoration are persistently activated following several repeated injuries, inducing deposition of extracellular matrix. (ECM). Factors responsible for ECM remodeling have been identified in a pathway involving a family of zinc-dependent enzyme matrix metalloproteinases (MMPs), together with tissue inhibitor of metalloproteinases (TIMPs). Recent experimental models suggested a role of CCR5 receptor in the genesis of liver fibrosis. Drawing from these background we decided to evaluate the effects of the treatment with the CCR5 inhibitor Maraviroc on LX-2, a human hepatic stellate cell line (HSC). Treatment with Maraviroc resulted in a block in S phase of LX-2 cells with increased expression levels of cyclin D1 and p21 while the expression of p53 was reduced. Treatment with Maraviroc was also able to block the accumulation of fibrillar collagens and extracellular matrix proteins (ECM), as demonstrated by the decrease of specific markers as Collagen type I, α-SMA, and TGF-β1. In addition we observed a down regulation of both metalloproteins (MMP-2, MMP-9), used for the degradation of the extracellular matrix and their inhibitors (TIMP-1, TIMP-2). The identification of a compound that may modulate the dynamic of liver fibrosis could be crucial in all chronic liver diseases. Maraviroc could play an important role because, in addition to its own anti-HIV activity, it could reduce the release of pro-inflammatory citokynes implicated in liver fibrogenesis.
在急性肝损伤后，组织再生通过降解沉积的纤维性物质来修复病变，而在多次重复损伤后，组织修复机制持续激活，导致细胞外基质（ECM）的沉积。已经在涉及锌依赖性酶基质金属蛋白酶（MMPs）家族和金属蛋白酶组织抑制剂（TIMPs）的途径中确定了负责 ECM 重塑的因素。最近的实验模型表明 CCR5 受体在肝纤维化的发生中起作用。根据这些背景，我们决定评估 CCR5 抑制剂马拉维罗治疗 LX-2（一种人肝星状细胞系（HSC））的效果。马拉维罗治疗导致 LX-2 细胞的 S 期阻滞，细胞周期蛋白 D1 和 p21 的表达水平增加，而 p53 的表达减少。马拉维罗治疗还能够阻止纤维胶原和细胞外基质蛋白（ECM）的积累，如特定标志物 Collagen type I、α-SMA 和 TGF-β1 的减少所证明的那样。此外，我们观察到两种金属蛋白酶（MMP-2、MMP-9）及其抑制剂（TIMP-1、TIMP-2）的下调。鉴定一种可能调节肝纤维化动态的化合物在所有慢性肝病中都可能至关重要。马拉维罗可能发挥重要作用，因为除了其自身的抗 HIV 活性外，它还可以减少参与肝纤维化发生的促炎细胞因子的释放。
