Liver Fibrosis: Understanding the Dynamics of Bidirectional Wound Repair to Inform the Design of Markers and Therapies

Abstract

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.