肝纤维化：从发病机制的新疗法

StephenW

Dig Dis. 2016;34(4):410-22. doi: 10.1159/000444556. Epub  2016 May 11.
Liver Fibrosis: From Pathogenesis to Novel Therapies.Weiskirchen R1, Tacke F.
Author information

• 1Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany.
  

AbstractChronic liver injury is accompanied by a dysbalanced scarring process, termed fibrosis. This process is mainly driven by chronic inflammation and an altered activity of a multitude of different chemokines and cytokines, resulting in the infiltration by immune cells (especially macrophages) and increase of matrix-expressing cell types. These processes might lead to cirrhosis representing the end-stage of fibrosis. Recent clinical studies comprising patients successfully treated for viral hepatitis showed that liver fibrogenesis and even cirrhosis may be reverted. The hepatic capacity to remodel scar tissue and to revert into a normal liver follows specific mechanistic principles that include the termination of chronic tissue damage, shifting the cellular bias from inflammation to resolution, initiation of myofibroblast apoptosis or senescence and, finally, fibrinolysis of excess scar tissue. The plurality of molecular and cellular triggers involved in initiation, progression and resolution of hepatic fibrogenesis offers an infinite number of therapeutic possibilities. For instance, inflammatory macrophages can be targeted via inhibition of chemokine CCL2 or its receptor CCR2 (e.g., by cenicriviroc) as well as by transfer of restorative macrophage subsets. Another target is galectin-3 that acts at various stages along the continuum from acute to chronic inflammation. Profibrogenic cytokines (e.g., transforming growth factor-β), matricellular proteins (e.g., CCN1/CYR61) or signaling pathways involved in fibrogenesis offer further possible targets. Other options are the application of therapeutic antibodies directed against components involved in biogenesis or remodeling of connective tissue such as lysyl oxidase-like-2 or synthetic bile acids like obeticholic acid that activate the farnesoid X receptor and was antifibrotic in a phase 2 study (FLINT trial). Factors affecting the gut barrier function or the intestinal microbiome further expanded the repertoire of drug targets. In this review, we discuss novel concepts in resolution of hepatic fibrosis and focus on drug targets that might be suitable to trigger resolution of fibrosis.
© 2016 S. Karger AG, Basel.

StephenW

挖派息。 2016年; 34（4）：410-22。 DOI：10.1159 / 000444556。 EPUB 2016年5月11日。
肝纤维化：从发病机制的新疗法。
威斯克辛R1，塔克F.
作者信息

    分子Pathobiochemistry，实验基因治疗和临床化学，大学RWTH亚琛医院，德国亚琛1Institute。

抽象

慢性肝损伤是伴随着dysbalanced结疤过程，称为纤维化。该过程主要由慢性炎症和不同的趋化因子和细胞因子，导致由免疫细胞（尤其是巨噬细胞）和基质表达的细胞类型的增加渗透的众多的改变的活性驱动。这些过程可能导致较纤维化的终末期肝硬化。最近，包括病毒性肝炎成功治疗患者的临床研究表明，肝纤维化，甚至肝硬化可以还原。重塑瘢痕组织并恢复成正常肝脏的肝容量如下特定机械原理，包括慢性的组织损伤过量瘢痕的终止，从炎症移蜂窝偏压到分辨率，成肌纤维细胞的细胞凋亡或衰老的开始和最后，纤溶组织。多个参与启动，进展和肝纤维化的分辨率分子和细胞触发提供了治疗的可能性无限多。例如，炎性巨噬细胞可以通过趋化因子CCL2或其受体CCR2（例如，通过cenicriviroc）的抑制，以及通过恢复性巨噬细胞子集的转移进行定位。另一个目标是半乳糖凝集素3其作用在沿连续由急性转为慢性炎症不同阶段。纤维化细胞因子（例如，转化生长因子β），matricellular蛋白（例如，CCN1 / CYR61）或信令参与纤维形成通路提供进一步的可能的目标。其他选项是针对涉及结缔组织的生物合成或重塑组件赖氨酰氧化酶样2或合成胆汁酸像obeticholic酸能激活法尼酯X受体和是在一个第2阶段研究的抗纤维化此类治疗性抗体的应用（FLINT试用版）。影响肠道屏障功能和肠道微生物因素进一步扩大的药物靶点的剧目。在这次审查中，我们在肝纤维化的分辨率讨论新概念，专注于药物靶点，可能是合适的触发纤维化的分辨率。

2016年©S.卡尔格公司，巴塞尔。

StephenW

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