Moderate Drinking, Inflammation, and Liver Disease

Currently accepted model of the pathomechanisms of alcoholic hepatitis. Chronic alcohol use is associated with increased endotoxin levels in the portal blood presumably from increased gut permeability. Endotoxin in the liver activates Kupffer cells, the resident macrophages, to produce chemokines (IL-8, MCP-1), proinflammatory cytokines (TNFα, IL-1), reactive oxygen species (ROS), and transforming growth factor β (TGFß). The chemokines recruit other inflammatory cells, particularly polymorphonuclear leukocytes (PMNL) into the liver, which amplify the inflammation. ROS and TNFα can damage hepatocytes by inducing apoptosis. In addition, alcohol and its metabolites have direct negative effects on hepatocyte function and survival. Moreover, Kupffer cell–derived inflammatory mediators, TGFβ, and LPS activate stellate cells to proliferate and produce collagen, leading to fibrosis and progression of liver damage.

Chronic alcohol feeding results in liver injury and inflammatory activation in mice. Mice (3–4 mice per group) were fed with a Lieber–de-Carli liquid diet containing 4.5% vol/vol alcohol, pair-fed liquid or chow diet. Top panels: Liver sections were stained with hematoxylin-eosin to demonstrate steatohepatitis. Bottom right: Serum ALT was determined using a commercially available kit demonstrating an increase in alcohol-fed mice. Bottom left: Nuclear extracts from livers were tested in an electromobility gel shift assay for NF-κB binding to a consensus NF-κB oligonucleotide as described (31), demonstrating an increase in NF-κB in alcohol-fed animals.

Acute alcohol administration inhibits NF-κB activation and LPS-induced TNFα production in mice. Mice (4–5 per group) were given acute alcohol (2 mL in intraperitoneal injection), followed by an LPS challenge. Serum and livers were collected 2 hours after the LPS administration. Right panel: Serum TNFα levels were determined by enzyme-linked immunosorbent assay demonstrating decreased TNFα in acute alcohol-treated mice. Left panel: Nuclear extracts from livers were evaluated for NF-κB activation in an electrophoretic mobility shift as described (31), demonstrating the decreased NF-κB in acute alcohol-treated mice.

Opposite effects of acute and chronic alcohol consumption on inflammation. Acute alcohol consumption has an anti-inflammatory effect through its effects on macrophages by inhibiting stimulation-induced proinflammatory pathways, while chronic alcohol use is associated with up-regulation of the same pathways in inflammatory cells.