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Review
. 2020 Apr 3;9(4):875.
doi: 10.3390/cells9040875.

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Natascha Roehlen  1   2 , Emilie Crouchet  1   2 , Thomas F Baumert  1   2   3
Affiliations
Review

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Natascha Roehlen et al. Cells. .

Abstract

Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.

Keywords: Hepatic stellate cell; Kupffer cell; PDGF; TGF-β; anti-fibrotics; liver cirrhosis; liver myofibroblast.

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Conflict of interest statement

The authors declare no conflict of interest. Inserm, the University of Strasbourg and IHU Strasbourg have filed patent applications with T.F.B. as a co-inventor on compounds for prevention and treatment of HCV infection, liver disease and HCC which have been licensed to Alentis Therapeutics, Basel.

Figures

Figure 1
Figure 1
Examples for mechanistic concepts for liver fibrosis. Chronic hepatocyte injury causes release of damage-associated patterns (DAMPs) and apoptotic bodies that activate Hepatic stellate cells (HSCs) and recruit immune cells. Complex multidirectional interactions between activated HSCs and Kupffer cells, as well as innate immune cells promote trans-differentiation into proliferative and extracellular matrix (ECM) producing myofibroblasts. Abbreviations: PDGF: Platelet Derived Growth Factor; TGF-β: Transforming Growth Factor Beta; CCL2: chemokine (C-C motif) ligand 2.
Figure 2
Figure 2
HSC activation and downstream pro-fibrogenic responses. Following the initial event of HSC activation, non-parenchymal cell directed pro- or anti-fibrogenic responses determine whether activated HSCs either transit into spontaneous resolution via reversion and apoptosis or pass into a perpetuated state that results in maintenance of a pro-inflammatory and pro-fibrogenic microenvironment as well as liver degrading ECM accumulation. Abbreviations: α-SMA: α-smooth muscle actin; DAMPS: Damage-associated molecular pattern; ECM: Extracellular matrix; HSC: hepatic stellate cells; PDGF: Platelet-derived growth factor; ROS: Reactive oxygen species; TGF-β: Transforming growth factor β.
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