Immune Function and Inflammation

The liver is the largest of the reticuloendothelial organs and has a prominent role in host defense. Kupffer cells account for nearly 10% of the hepatic mass. These cells filter splanchnic venous blood before it reaches the central circulation, phagocytizing and processing antigens and other substances absorbed from the gastrointestinal tract.^[140] In sepsis, Kupffer cells are responsible for scavenging bacteria, inactivating bacterial products, and clearing inflammatory mediators.^[141] Kupffer cell activation (e.g., by inflammatory stimuli) produces or triggers the release of proinflammatory substances (reduced oxygen species, nitro-radicals, leukotrienes, proteases), including cytokines and chemokines, which recruit neutrophils to the liver and heighten the inflammatory response.^[141] Although Kupffer cells are essential for defending the body against foreign intrusions, their activation can also harm the liver when they induce, or exacerbate, hepatocellular injury in diseases involving the liver.^{[141] [142] [143] [144] [145]} During oxidative stress, endothelial cells of the hepatic sinusoids or terminal hepatic veins are vulnerable to toxic injury because of their low glutathione content. ^[146] These cells may be a pathogenic focus of drug-induced vascular injury. Hepatic stellate cells are the principal liver cell type involved in matrix deposition and hepatic fibrosis. Activated stellate cells (as occurs in methotrexate-induced hepatic fibrosis) may be transformable by certain drugs into collagen-synthesizing myofibroblasts.