Abstract
Liver fibrosis is a wound-healing process in response to repeated and chronic injury to hepatocytes and/or cholangiocytes. Ongoing hepatocyte apoptosis or necrosis lead to increase in ROS production and decrease in antioxidant activity, which recruits inflammatory cells from the blood and activate hepatic stellate cells (HSCs) changing to myofibroblasts. Injury to cholangiocytes also recruits inflammatory cells to the liver and activates portal fibroblasts in the portal area, which release molecules to activate and amplify cholangiocytes. No matter what origin of myofibroblasts, either HSCs or portal fibroblasts, they share similar characteristics, including being positive for α-smooth muscle actin and producing extracellular matrix. Based on the extensive pathogenesis knowledge of liver fibrosis, therapeutic strategies have been designed to target each step of this process, including hepatocyte apoptosis, cholangiocyte proliferation, inflammation, and activation of myofibroblasts to deposit extracellular matrix, yet the current therapies are still in early-phase clinical development. There is an urgent need to translate the molecular mechanism of liver fibrosis to effective and potent reagents or therapies in human.
Highlights
Liver fibrosis is a wound-healing process of the liver in response to repeated and chronic liver injury with distinct etiologies, such as infectious diseases, metabolic derangements, exposure to chemicals, or autoimmune diseases
CXCR2-formyl-peptide receptor 1 (FPR1) antagonism can block neutrophil infiltration and hepatotoxicity in acetaminophen-induced liver injury (Marques et al, 2012). These findings suggest blocking P2X7R and/or CXCR2-FPR1 could be a promising therapeutic approach to control liver inflammation
Pharmacological inhibition of TLR4 by Eritoran tetrasodium ameliorates liver injury through blocking high mobility group box-1 (HMGB1)-mediated inflammatory signaling in ischemia and reperfusion mice (McDonald et al, 2015) In addition, both bacterial DNA and mitochondrial DNA and nuclear DNA released by damaged hepatocyte can activate TLR9 and induce a number of cellular immune responses (Kubes and Mehal, 2012)
Summary
Ping Wang 1, 2, 3, Yukinori Koyama 1, 2, 4, Xiao Liu 1, 2, Jun Xu 1, 2, Hsiao-Yen Ma 1, 2, Shuang Liang 1, 2, In H. Liver fibrosis is a wound-healing process in response to repeated and chronic injury to hepatocytes and/or cholangiocytes. Ongoing hepatocyte apoptosis or necrosis lead to increase in ROS production and decrease in antioxidant activity, which recruits inflammatory cells from the blood and activate hepatic stellate cells (HSCs) changing to myofibroblasts. Injury to cholangiocytes recruits inflammatory cells to the liver and activates portal fibroblasts in the portal area, which release molecules to activate and amplify cholangiocytes. No matter what origin of myofibroblasts, either HSCs or portal fibroblasts, they share similar characteristics, including being positive for α-smooth muscle actin and producing extracellular matrix. Based on the extensive pathogenesis knowledge of liver fibrosis, therapeutic strategies have been designed to target each step of this process, including hepatocyte apoptosis, cholangiocyte proliferation, inflammation, and activation of myofibroblasts to deposit extracellular matrix, yet the current therapies are still in early-phase clinical development.
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