A comprehensive review of the classical prescription Yiguan Jian: Phytochemistry, quality control, clinical applications, pharmacology, and safety profile

Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.

The progression of chronic liver diseases (CLD), irrespective of etiology, involves chronic parenchymal injury, persistent activation of inflammatory response as well as sustained activation of liver fibrogenesis and wound healing response. Liver fibrogenesis, is a dynamic, highly integrated molecular, cellular and tissue process responsible for driving the excess accumulation of extracellular matrix (ECM) components (i.e., liver fibrosis) sustained by an eterogeneous population of hepatic myofibroblasts (MFs). The process of liver fibrogenesis recognizes a number of common and etiology-independent mechanisms and events but it is also significantly influenced by the specific etiology, as also reflected by peculiar morphological patterns of liver fibrosis development. In this review we will analyze the most relevant established and/or emerging pathophysiological issues underlying CLD progression with a focus on the role of critical hepatic cell populations, mechanisms and signaling pathways involved, as they represent potential therapeutic targets, to finally analyze selected and relevant clinical issues.

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.