Abstract
Fibrogenic progression of chronic liver disease, whatever the etiology, is characterized by persistent chronic parenchymal injury, chronic activation of inflammatory response, and sustained activation of liver fibrogenesis, and of pathological wound healing response. A critical role in liver fibrogenesis is played by hepatic myofibroblasts (MFs), a heterogeneous population of α smooth-muscle actin—positive cells that originate from various precursor cells through a process of activation and transdifferentiation. In this review, we focus the attention on the role of extracellular signal-regulated kinase (ERK) signaling pathway as a critical one in modulating selected profibrogenic phenotypic responses operated by liver MFs. We will also analyze major therapeutic antifibrotic strategies developed in the last two decades in preclinical studies, some translated to clinical conditions, designed to interfere directly or indirectly with the Ras/Raf/MEK/ERK signaling pathway in activated hepatic MFs, but that also significantly increased our knowledge on the biology and pathobiology of these fascinating profibrogenic cells.
Highlights
Fibrogenic Progression of Chronic Liver DiseasesProgression of chronic liver diseases (CLD), whatever the etiology, is typically characterized by an interrelated vicious circle involving persistent chronic parenchymal injury, chronic activation of inflammatory response, and sustained activation of liver fibrogenesis, and of pathological wound healing response
We focus the attention on the role of extracellular signal-regulated kinase (ERK) signaling pathway as a critical one in modulating selected profibrogenic phenotypic responses operated by liver MFs
To interfere with mechanisms resulting in dysregulation of critical molecular pathways in activated hepatic stellate cells (HSC) or MFs; this approach is by far the most interesting, with several studies dedicated to either blocking pathways elicited by ligand-receptor interactions, including those elicited by transforming growth factor-β1 (TGFβ1), platelet-derived growth factors (PDGF), ligand-receptor-induced signalling pathways, HGF, VEGF/VEGFR, Wnt/β-catenin, EGF/EGFR, Hedgehog, endotelins, cannabinoids, adipokines, retinoid, and vitamin D receptors, integrins, and toll-like receptors (TLRs) [5,6,7,22];
Summary
Progression of chronic liver diseases (CLD), whatever the etiology, is typically characterized by an interrelated vicious circle involving persistent chronic parenchymal injury, chronic activation of inflammatory response, and sustained activation of liver fibrogenesis, and of pathological wound healing response. The activation of innate and adaptive immune cells, occurring through the release of several soluble peptide mediators (cytokines, growth factors, chemokines) and reactive oxygen species (ROS) generation is critical in initiating and perpetuating the activation of pro-fibrogenic hepatic MFs [7,18,19]. During CLD progression, MFs can actively integrate (and respond to) an impressive scenario of incoming “signals” (i.e., growth factors, cytokines, chemokines, ROS, adipokines, etc) These signals are released by liver cell populations (hepatocytes, Kupffer cells, sinusoidal endothelial cells or SEC, cholangiocytes, hepatic progenitor cells or HPC, resident lymphocytes) as well as by cells infiltrating innate and adaptive immune cells recruited into injured liver. Any significant increase in intracellular ROS levels in activated MFs can result in enhanced migration of these cells, as shown in pro-fibrogenic cells exposed to hypoxic conditions (i.e., conditions in which an increased release of mitochondrial ROS has been described) [47]
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