NOX does not play a role in experimental steatosis and the generation of ROS in hepatocytes, but exerts a key role in fibrosis. (HEPATOLOGY 2010;) Liver fibrosis is the consequence of chronic liver injury and represents an important cause of mortality worldwide.1, 2 Liver fibrosis results from inflammation
associated with the production of chemokines and cytokines that stimulate and act on different cells in the liver, including hepatic stellate cells (HSCs), Kupffer cells (KCs), Selleck Ibrutinib hepatocytes (HEPs), and endothelial cells.3, 4 The endpoint of advanced liver fibrosis is cirrhosis, in which the fibrous scar and regenerating nodules lead to hepatocellular dysfunction, portal hypertension, and hepatocellular carcinoma.5, 6 An inflammation–fibrosis–cancer axis has therefore been proposed.7 Oxidative stress plays an important role in inflammation, fibrosis, and cancer.8-10 Nicotinamide adenine dinucleotide phosphate (NADPH)
oxidase (NOX), a key source of reactive oxygen species (ROS) in the liver,11 PS-341 molecular weight may therefore represent an important new therapeutic target.12 NOX is a multiprotein complex that catalyzes ROS formation in response to many stimuli.9, 13 Macrophages, including KCs, express the phagocytic form of NOX that plays a crucial role in antimicrobial
defense.8, 14-16 Guanylate cyclase 2C The nonphagocytic form of NOX is expressed in other cell types, such as vascular smooth muscle cells and cardiac myofibroblasts, and is required for the proper activation of many intracellular signalling pathways, including mitogen-activated protein kinase and phosphoinositide 3-kinase.11, 17, 18 We have previously shown that NOX is required for hepatic fibrosis in vivo.9 KCs express the majority of NOX in the liver and play an important role in HSC activation.19 However, NOX is also expressed by HSCs and is able to mediate HSC activation in response to fibrogenic agonists such as platelet-derived growth factor, angiotensin II, and leptin.9, 18, 20 Furthermore, HEPs contain NOX,21 providing a potentially additional sources of ROS in inflammation and fibrosis. However, the relative contribution of NOX in KCs, HEPs, and HSCs to hepatic inflammation and fibrosis remains unknown. This study demonstrates that NOX-mediated formation of ROS in non–bone marrow (BM)-derived liver cells plays a key role in liver fibrosis.
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