Abstract
Chronic liver injury, resulted from different etiologies (e.g., virus infection, alcohol abuse, nonalcoholic steatohepatitis (NASH) and cholestasis) can lead to liver fibrosis characterized by the excess accumulation of extracellular matrix (ECM) proteins (e.g., type I collagen). Hepatic myofibroblasts that are activated upon liver injury are the key producers of ECM proteins, contributing to both the initiation and progression of liver fibrosis. Hepatic stellate cells (HSCs) and to a lesser extent, portal fibroblast, are believed to be the precursor cells that give rise to hepatic myofibroblasts in response to liver injury. Although, much progress has been made toward dissecting the lineage origin of myofibroblasts, how these cells are activated and become functional producers of ECM proteins remains incompletely understood. Activation of myofibroblasts is a complex process that involves the interactions between parenchymal and non-parenchymal cells, which drives the phenotypic change of HSCs from a quiescent stage to a myofibroblastic and active phenotype. Accumulating evidence has suggested a critical role of NADPH oxidase (NOX), a multi-component complex that catalyzes reactions from molecular oxygen to reactive oxygen species (ROS), in the activation process of hepatic myofibroblasts. NOX isoforms, including NOX1, NOX2 and NOX4, and NOX-derived ROS, have all been implicated to regulate HSC activation and hepatocyte apoptosis, both of which are essential steps for initiating liver fibrosis. This review highlights the importance of NOX isoforms in hepatic myofibroblast activation and the progression of liver fibrosis, and also discusses the therapeutic potential of targeting NOXs for liver fibrosis and associated hepatic diseases.
Highlights
The main causes of hepatic fibrosis are chronic hepatitis B and C infection, autoimmune and biliary diseases, alcoholic steatohepatitis (ASH) and, increasingly, nonalcoholic steatohepatitis (NASH) (Bataller and Brenner, 2005)
Dying hepatocyte can release damage-associated molecular patterns (DAMPs) that induce the secretion of cytokines and chemokines from KCs/macrophage that eventually results in Hepatic stellate cells (HSCs) activation and liver fibrosis
NOX4 promotes myofibroblasts activation and hepatic fibrosis through at least two distinct mechanisms: (1) directly facilitating TGFβ-induced HSC activation and production of profibrogenic targets, (2) indirectly promoting TGFβ or death ligandinduced hepatocytes apoptosis, which contributes to the production of cytokines, chemokines, and microparticles that leads to HSC activation (Aoyama et al, 2012; Jiang et al, 2012)
Summary
The main causes of hepatic fibrosis are chronic hepatitis B and C infection, autoimmune and biliary diseases, alcoholic steatohepatitis (ASH) and, increasingly, nonalcoholic steatohepatitis (NASH) (Bataller and Brenner, 2005). NADPH Oxidases in Myofibroblasts Activation (Friedman, 2000) These processes facilitate the transition from liver fibrosis to cirrhosis, which may progress to more serious complications, such as portal hypertension due to increased resistance to portal blood flow, spontaneous bacterial peritonitis, and hepatic encephalopathy. Quiescent HSCs positive for adipocytes markers (PPARγ, SREBP-1c, and leptin) are the major cell type responsible for vitamin A storage (Bataller and Brenner, 2005). Reactive oxygen species (ROS) mediate the progression of hepatic fibrosis by stimulating the production of profibrogenic mediators from Kupffer cells and circulating inflammatory cells and by directly activating HSCs to induce their trans-differentiation into myofibroblasts (Sánchez-Valle et al, 2012). This review will focus on summarizing the roles of NOX isoforms that are distinctly expressed in different cell types in the liver
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