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.
Highlights
Chronic liver diseases are a major global health burden and account for approximately 2 million deaths per year worldwide [1]
Another recent example of mutual stimulation between Hepatic stellate cells (HSCs) and Kupffer cells was reported by Cai et al.They demonstrated that CXCL6 plays an important role in liver fibrosis through stimulating the release of TGF-β by Kupffer cells via an EGFR-dependent pathway [91]
While nucleos(t)ide analogues rarely result in viral cure, suppression of viral replication slows down disease progression, that can eventually end in liver cirrhosis and hepatocellular carcinoma (HCC) [191]
Summary
Chronic liver diseases are a major global health burden and account for approximately 2 million deaths per year worldwide [1]. Toxic, metabolic, or viral diseases lead to damaged hepatocytes and infiltration of immune cells that activate transdifferentiation. In chronic fibrogenic mechanisms causesof persistent activation of proliferating, contractile,causes and migrating liver diseases an imbalance pro-fibrogenic and anti-fibrogenic mechanisms persistent myofibroblasts that lead to contractile, excessive production of ECM [8,9]. The liver’s fatetotoexcessive either pass into an activation of proliferating, and migrating myofibroblasts that lead production anti-fibrotic scar-dissolving stage or to pass proceed an uninhibited fibrosis-promoting is hereby of ECM [8,9]. On(MMPs) the molecular a complex network resolution of due to expression of matrix-metalloproteinases [15,16].basis, On the molecular basis, a of cytokine-induced signaling pathways orchestrate cell interactions. Anti-fibrotic strategies and agents in clinical development are discussed
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