Important mechanisms responsible for alcohol-induced liver injury include mitochondrial damage and loss of ATP, formation of acetaldehyde- and other aldehyde-protein adducts, release of reactive oxygen species (ROS) from mitochondrial electron transfer chain, CYP2E1, and activated Kupffer cells (KCs); weakening of antioxidant defense systems; and increased intestinal permeability with endotoxemia. Endotoxin interacts with ethanol and/or acetaldehyde, and such interaction leads to a complex cascade of autocrine and paracrine pathways that involve the release of cytokines (proinflammatory, anti-inflammatory, and mutagenic), chemokines, and eicosanoids. These pathways are mediated by activation of KCs, induction of proliferation, and other phenotype changes in hepatic stellate cells (HSCs) leading to transformation to myofibroblasts (the latter is responsible for fibrogenesis, chemotaxis, and contractility, therefore contributing to portal hypertension, angiogenic response, and release of additional cytokines), and stimulation of sinusoidal cells (SECs) to release adhesive molecules and cytokines. Recent data implicate 8 likely role of apoptosis as a mechanism of hepatocyte cell death in alcoholic liver disease.
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