Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Germany.
Dept. of Medicine III, University Hospital Aachen, Germany.
Mol Aspects Med. 2019 Feb;65:2-15. doi: 10.1016/j.mam.2018.06.003. Epub 2018 Jun 30.
Fibrosis denotes excessive scarring, which exceeds the normal wound healing response to injury in many tissues. Although the extracellular matrix deposition appears unstructured disrupting the normal tissue architecture and subsequently impairing proper organ function, fibrogenesis is a highly orchestrated process determined by defined sequences of molecular signals and cellular response mechanisms. Persistent injury and parenchymal cell death provokes tissue inflammation, macrophage activation and immune cell infiltration. The release of biologically highly active soluble mediators (alarmins, cytokines, chemokines) lead to the local activation of collagen producing mesenchymal cells such as pericytes, myofibroblasts or Gli1 positive mesenchymal stem cell-like cells, to a transition of various cell types into myofibroblasts as well as to the recruitment of fibroblast precursors. Clinical observations and experimental models highlighted that fibrosis is not a one-way road. Specific mechanistic principles of fibrosis regression involve the resolution of chronic tissue injury, the shift of inflammatory processes towards recovery, deactivation of myofibroblasts and finally fibrolysis of excess matrix scaffold. The thorough understanding of common principles of fibrogenic molecular signals and cellular mechanisms in various organs - such as liver, kidney, lung, heart or skin - is the basis for developing improved diagnostics including biomarkers or imaging techniques and novel antifibrotic therapeutics.
纤维化表示过度的瘢痕形成，这种瘢痕形成超过了许多组织中正常的创伤愈合反应。尽管细胞外基质的沉积看起来没有结构，破坏了正常的组织结构，随后损害了适当的器官功能，但纤维化是一个高度协调的过程，由特定的分子信号和细胞反应机制的定义序列决定。持续的损伤和实质细胞死亡会引发组织炎症、巨噬细胞激活和免疫细胞浸润。生物活性高的可溶性介质（警报素、细胞因子、趋化因子）的释放导致局部激活产生胶原的间充质细胞，如周细胞、肌成纤维细胞或Gli1 阳性间充质干细胞样细胞，使各种细胞类型向肌成纤维细胞转化，并招募成纤维细胞前体。临床观察和实验模型强调，纤维化不是一条单行道。纤维化消退的特定机制原则涉及慢性组织损伤的解决、炎症过程向恢复的转变、肌成纤维细胞的失活以及最终多余基质支架的纤维溶解。深入了解不同器官（如肝、肾、肺、心或皮肤）中纤维生成分子信号和细胞机制的共同原则，是开发改进的诊断方法（包括生物标志物或成像技术）和新型抗纤维化治疗方法的基础。
