Liver Fibrosis: Understanding the Dynamics of Bidirectional Wound Repair to Inform the Design of Markers and Therapies
Liver Fibrosis: Understanding the Dynamics of Bidirectional Wound Repair to Inform the Design of Markers and Therapies
复制标题
DOI：
10.1159/000456581
复制
发表时间：
2017-01-01
影响因子：
2.3
通讯作者：
Fallowfield, Jonathan A.
中科院分区：
文献类型：
--
作者：
Iredale, John P.;Pellicoro, Antonella;Fallowfield, Jonathan A.
背景：肝纤维化是反复或慢性肝损伤的最终共同途径。当它发展到晚期时，肝硬化发展，这表明正常肝脏结构的丧失，正常血流的中断，增殖性肝细胞结节的发展和随之而来的功能衰竭。肝硬化还与危及生命的并发症有关。重要的是，这种血流失调包括由结构破坏和门脉压力的动态升高引起的变化，部分由肌成纤维细胞的收缩介导，肌成纤维细胞是纤维形成过程的主要细胞介质，来源于肝星状细胞（HSC），被称为活化的HSC（肌成纤维细胞/活化的HSC）。目前，来自啮齿动物和人类模型的令人信服的数据表明，肝纤维化是双向的。通过研究进行性和退行性肝纤维化模型，有可能确定可能成为治疗靶点的介质。可以说，通过识别导致正常结构恢复的自发消退的介质，可以定义高效抗纤维化或促消退治疗的属性。在这些关键属性中，了解基质降解酶及其抑制剂（分别为金属蛋白酶和金属蛋白酶组织抑制剂（TIMPs））的平衡，可以确定治疗靶点和TIMP-1作为纤维化血清标志物的价值。此外，一种潜在的治疗剂松弛素（RLN）通过其同源的g蛋白偶联受体（RXFP1）在活化的HSC表面的作用显示出前景。rln - rxfp1介导的通路的激活可以通过测量活化的HSC的动态收缩力以及随之产生的门静脉压力和血流的变化来检测，作为一种响应性的物理生物标志物。结论：通过对进展性肝纤维化的认识和解决，我们确定了一系列的治疗靶点。与此同时，纤维化的关键介质可能作为可溶性或物理生物标志物发挥着不可或缺的作用。(C) 2017 S. Karger AG，巴塞尔
Background: Liver fibrosis is the final common pathway of iterative or chronic liver damage. When it reaches an advanced stage, cirrhosis develops and this indicates a loss of normal liver architecture, disruption of normal blood flow, the development of nodules of proliferative hepatocytes and consequent functional failure. Cirrhosis is also associated with life-threatening complications. Importantly, this dysregulation of blood flow involves changes resulting from both architectural disruption and a dynamic rise in portal pressure mediated in part by the contraction of myofibroblasts - the major cell mediator of the fibrogenic process which are derived from hepatic stellate cells (HSC) and termed activated HSC (myofibroblast/activated HSC). Key Messages: There is now compelling data from both rodent and human models that liver fibrosis is bidirectional. By studying models of progressive and regressing liver fibrosis it has been possible to identify mediators that may be therapeutic targets. Arguably, by identifying the mediators of spontaneous resolution that result in a return of normal architecture, the attributes of a highly effective antifibrotic or pro resolution therapy can be defined. Among these key attributes, understanding the balance of matrix-degrading enzymes and their inhibitors (the metalloproteinases and Tissue inhibitors of metalloproteinases (TIMPs), respectively) led to the identification of both therapeutic targets and the value of TIMP-1 as a serum marker of fibrosis. Furthermore, the action of a potential therapeutic agent, relaxin (RLN) acting through its cognate G-protein coupled receptor (RXFP1) on the surface of activated HSC shows promise. Activation of the RLN-RXFP1-mediated pathway can be detected in vivo by measuring the dynamic contractility of activated HSC and the consequent changes in portal pressure and blood flow as a responsive physical biomarker. Conclusion: By understanding progressive and resolving liver fibrosis, a series of therapeutic targets have been identified. At the same time, key mediators of fibrosis may have an integral role to play as soluble or physical biomarkers. (C) 2017 S. Karger AG, Basel