Weiskirchen Ralf, Tacke Frank
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany.
Dig Dis. 2016;34(4):410-22. doi: 10.1159/000444556. Epub 2016 May 11.
Chronic 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.
慢性肝损伤伴随着一种失衡的瘢痕形成过程，即纤维化。这个过程主要由慢性炎症以及多种不同趋化因子和细胞因子活性的改变所驱动，导致免疫细胞（尤其是巨噬细胞）浸润以及表达基质的细胞类型增加。这些过程可能会导致肝硬化，而肝硬化代表纤维化的终末期。最近针对成功治疗的病毒性肝炎患者的临床研究表明，肝纤维化甚至肝硬化可能会逆转。肝脏重塑瘢痕组织并恢复为正常肝脏的能力遵循特定的机制原则，包括终止慢性组织损伤、将细胞偏向从炎症转变为炎症消退、启动肌成纤维细胞凋亡或衰老，以及最终对多余瘢痕组织进行纤维蛋白溶解。参与肝纤维化起始、进展和消退的多种分子和细胞触发因素提供了无数的治疗可能性。例如，炎症巨噬细胞可以通过抑制趋化因子CCL2或其受体CCR2（例如通过塞尼卡维罗）以及通过转移恢复性巨噬细胞亚群来靶向。另一个靶点是半乳糖凝集素-3，它在从急性炎症到慢性炎症连续过程的各个阶段都起作用。促纤维化细胞因子（例如转化生长因子-β）、基质细胞蛋白（例如CCN1/CYR61）或参与纤维化形成的信号通路提供了更多可能的靶点。其他选择包括应用针对参与结缔组织生物合成或重塑的成分的治疗性抗体，如赖氨酰氧化酶样-2，或合成胆汁酸，如奥贝胆酸，它激活法尼醇X受体，并且在一项2期研究（FLINT试验）中具有抗纤维化作用。影响肠道屏障功能或肠道微生物群的因素进一步扩大了药物靶点的范围。在这篇综述中，我们讨论肝纤维化消退的新概念，并关注可能适合触发纤维化消退的药物靶点。
