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.

Effect of Orally Administered Relaxin in Experimental Nash <strong> </strong>

“…The anti-fibrotic activity of RLX, previously showed in several organs, makes its potential effect in liver diseases worth exploring [3,6,8]. Treatment of fibrosis and its progression to cirrhosis is still an unmet need in the management of chronic liver diseases [23][24][25]. In this regard, we have investigated the efficacy of RLX in preventing the onset and progression of fibrosis in a mouse model of NASH, currently the most prevalent chronic liver disease [12][13].…”

Obeticholic acid and INT-767 modulate collagen deposition in a NASH in vitro model

“…MMPs are released into the extracellular environment where they contribute to collagen turnover. Their activity is finely regulated both at mRNA and at post-transcriptional level by the interaction with the tissue inhibitor of metalloproteinase proteins (TIMPs) 24 . After 96 hours, MMPs activity was significantly reduced in the cells treated with FFAs (p < 0.05 compared to CTRL).…”

Puerarin alleviates liver fibrosis via inhibition of the ERK1/2 signaling pathway in thioacetamide‑induced hepatic fibrosis in rats

“…In addition, it has been demonstrated that the progression of liver fibrosis is reversible (11)(12)(13)(14). There are several therapeutic agents, including Orlistat, Metformin and Candesartan, typically used for anti-fibrotic therapy (15,16). However, the major limitation is the lack of effective treatment strategies for liver fibrosis (17,18).…”