Molecular pathogenesis of alcohol-induced hepatic fibrosis.
Alcohol abuse is a main cause of liver fibrosis and cirrhosis in the western world. Although the major mechanisms of fibrogenesis are independent of the origin of liver injury, alcoholic liver fibrosis features distinctive characteristics, including the pronounced inflammatory response of immune cells due to elevated gut-derived endotoxin plasma levels, increased formation of reactive oxygen species (ROS), ethanol-induced pericentral hepatic hypoxia or formation of cell-toxic and pro-fibrogenic ethanol metabolites (e.g., acetaldehyde or lipid oxidation products). These factors are together responsible for increased hepatocellular cell death and activation of hepatic stellate cells (HSCs), the key cell type of liver fibrogenesis. To date, removing the causative agent is the most effective intervention to prevent the manifestation of liver cirrhosis. A novel experimental approach in fibrosis therapy is the selective induction of cell death in HSCs. Substances such as gliotoxin, anandamide or antibody against tissue inhibitor of metalloproteinase (TIMP)-1 can selectively induce cell death in activated HSCs. These new results in basic science are encouraging for the search of new antifibrotic treatment.
Siegmund
Sören V
SV
Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
Brenner
David A
DA
D000818:Animals; D017209:Apoptosis; D001095:Arachidonic Acids / Q000627:therapeutic use; D063388:Endocannabinoids; D005109:Extracellular Matrix / Q000473:pathology; D005912:Gliotoxin; D006801:Humans; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008104:Liver Cirrhosis, Alcoholic / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D018384:Oxidative Stress / Q000502:physiology; D053284:Polyunsaturated Alkamides; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000627:therapeutic use
D001095:Arachidonic Acids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D019715:Tissue Inhibitor of Metalloproteinase-1; D005912:Gliotoxin; C078814:anandamide