Liver Fibrosis: From Pathogenesis to Novel Therapies

Abstract

Chronic liver injury is accompanied by a dysbalanced scarring process, termed fibrosis. This process is mainly driven by chronic inflammation and an altered activity of a multitude of different chemokines and cytokines, resulting in the infiltration by immune cells (especially macrophages) and increase of matrix-expressing cell types. These processes might lead to cirrhosis representing the end-stage of fibrosis. Recent clinical studies comprising patients successfully treated for viral hepatitis showed that liver fibrogenesis and even cirrhosis may be reverted. The hepatic capacity to remodel scar tissue and to revert into a normal liver follows specific mechanistic principles that include the termination of chronic tissue damage, shifting the cellular bias from inflammation to resolution, initiation of myofibroblast apoptosis or senescence and, finally, fibrinolysis of excess scar tissue. The plurality of molecular and cellular triggers involved in initiation, progression and resolution of hepatic fibrogenesis offers an infinite number of therapeutic possibilities. For instance, inflammatory macrophages can be targeted via inhibition of chemokine CCL2 or its receptor CCR2 (e.g., by cenicriviroc) as well as by transfer of restorative macrophage subsets. Another target is galectin-3 that acts at various stages along the continuum from acute to chronic inflammation. Profibrogenic cytokines (e.g., transforming growth factor-β), matricellular proteins (e.g., CCN1/CYR61) or signaling pathways involved in fibrogenesis offer further possible targets. Other options are the application of therapeutic antibodies directed against components involved in biogenesis or remodeling of connective tissue such as lysyl oxidase-like-2 or synthetic bile acids like obeticholic acid that activate the farnesoid X receptor and was antifibrotic in a phase 2 study (FLINT trial). Factors affecting the gut barrier function or the intestinal microbiome further expanded the repertoire of drug targets. In this review, we discuss novel concepts in resolution of hepatic fibrosis and focus on drug targets that might be suitable to trigger resolution of fibrosis.

Clinical relevance of Cyr61 expression in patients with hormone-dependent breast cancer

“…with hormone-dependent breast cancer including angiogenesis (7,10); however, the alteration of Cyr61 expression has been demonstrated to be associated with a number of pathologies (11)(12)(13), including malignant neoplasms (14,15). In previous studies by our group, Cyr61 expression profiling in BC and its functional expression regulation was examined (16,17) demonstrating a stage-dependent induction of Cyr61 in BC tumorigenesis and hypoxia-induced alternative splicing of Cyr61 in tumor cells.…”

Hepatic stellate cells as key target in liver fibrosis

“…As summarized in this review, comprehensive characterization of molecular dysregulation of HSCs and their functional assessment in engineered animal models have elucidated multiple candidate therapeutic targets and strategies, many of which are currently under evaluation in patients with chronic liver diseases [324]. However, both fibrogenesis and fibrosis regression involve highly heterogeneous and evolving cell populations whose interactions have not yet fully characterized.…”

Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets

“…The main etiologies of liver fibrosis are schistosome and chronic viral hepatitis infection, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and cholestatic and autoimmune liver disease[1,14-17]. Liver fibrosis, which is characterized by the excessive deposition ECM proteins[18], involves both parenchymal and nonparenchymal hepatic cells, as well as infiltrating immune cells[3,19].…”

“…Cirrhosis is a major health problem worldwide, owing to the lack of effective treatment methods[1,2]. During hepatic fibrosis, continuous accumulation of extracellular matrix (ECM) extremely rich in collagen I and III leads to scar deposition and liver fibrosis[3,4].…”