Alcoholic hepatitis is a disease that is characterized histologically by marked polymorphonuclear leukocyte infiltration of the liver, necrosis of liver cells and fibrosis. Clinically, it produces fever, leukocytosis, impaired liver function and significant mortality or later morbidity (cirrhosis). Despite considerable work it is not known how alcohol causes acute inflammation in the liver. Recent studies, however, have indicated that hepatocytes metabolizing ethanol in vitro release a chemoattractant substance which can stimulate migration of PMN. The substance appears to be a leukotriene - one of an important class of mediators of inflammation discovered only five years ago. It may be hypothesized that generation of the chemotactic substance is the initial step in alcohol-related liver damage. It draws in leukocytes which then attack liver cells and release soluble mediators that stimulate collagen synthesis. Normal control mechanisms may include inactivation of the chemoattractant by cells or plasma. The experiments proposed here will conclusively identify the chemical structure of the chemoattractant, determine how ethanol metabolism is involved in its generation and explore the effect of the chemoattractant on processes related to inflammation such as toxicity of leukocytes for hepatocytes and production of connective tissue components (collagen) by cells from the liver. Newer inhibitors of leukotrienes will be tested for ability to interrupt damaging effects. The reults should provide fresh hypotheses about the mechanism of alcohol-related liver injury and, if specific inhibitors of leukotriene generation are developed, it may lead to more successful modes of therapy than are currently available.
