Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF‐β as major players and therapeutic targets

Abstract

Hepatic fibrosis is a scarring process that is associated with an increased and altered deposition of extracellular matrix in liver. At the cellular and molecular level, this progressive process is mainly characterized by cellular activation of hepatic stellate cells and aberrant activity of transforming growth factor-β1 and its downstream cellular mediators. Although the cellular responses to this cytokine are complex, the signalling pathways of this pivotal cytokine during the fibrogenic response and its connection to other signal cascades are now understood in some detail. Based on the current advances in understanding the pleiotropic reactions during fibrogenesis, various inhibitors of transforming growth factor-β were developed and are now being investigated as potential drug candidates in experimental models of hepatic injury. Although it is too early to favour one of these antagonists for the treatment of hepatic fibrogenesis in human, the experimental results obtained yet provide stimulatory impulses for the development of an effective treatment of choice in the not too distant future. The present review summarises the actual knowledge on the pathogenesis of hepatic fibrogenesis, the role of transforming growth factor-β and its signalling pathways in promoting the fibrogenic response, and the therapeutic modalities that are presently in the spotlight of many investigations and are already on the way to take the plunge into clinical studies.

Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats

“…31 As the expression of PDGFbR (a proliferation marker) and a-SMA (a MFB marker) were significantly decreased (Figure 1), the most likely explanation is inhibition of HSC activation. 4,6 Supporting this assumption, atorvastatin-incubated MFB expressed less profibrotic cytokines and collagen (Figure 2). …”

“…4,5 MFB express a-smooth muscle actin (a-SMA), which is used as a marker of their activation. 2,6,7 Statins have shown beneficial effects on hepatic fibrosis and portal hypertension in cirrhosis, most likely because the inhibition of HMG-CoA-reductase impedes small GTPases (RhoA and Ras). [8][9][10][11][12][13] The portal pressure-lowering effect was attributed to the inhibition of RhoA translocation to the membrane of myofibroblastic HSC and thereby disruption of RhoA/Rho-kinase signaling, resulting in decreased contraction of these cells and reduced intrahepatic resistance.…”

Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis

“…Next, we measured the mRNA level of TGF-␤1, which is a potent profibrogenic mediator that activates HSCs. 28,29 TGF-␤1 was increased 2-fold in PiZ BDL mice when compared with wild-type BDL mice (P ϭ 0.03; Fig. 5C).…”

Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis

“…Activated HSCs are the major source of ECM [50][51][52] . Increased expression of α-SMA, a marker of transdifferentiation, is one of the major phenotypic changes that activated HSCs display [53][54][55] .…”