The overall objective of this proposal is to elucidate the role of inflammatory neutrophils and activated Kupffer and endothelial cells on the induction of hepatotoxicity in chronic alcoholics, with a view to developing immunotherapeutic and biotechnological methods for the treatment of tissue injury after prolonged alcohol consumption. This proposal is based on the hypothesis that chronic alcohol intoxication regulates the expression of adhesion molecules and leukocyte infiltration into the liver. Such event may also be mediated by the release of chemotractant factors released by hepatocytes, Kupffer and endothelial cells after exposure to ethanol. As a consequence, a wide spectrum of bioactive substances are released that may contribute to the initiation of hepatic injury in susceptible individuals. It is also hypothesized that such events may be exacerbated by endotoxin.
Specific aim I will investigate the expression of adhesion molecules, i.e., Beta2-integrins and selectins on neutrophils and their counterreceptors on Kupffer, endothelial cells and hepatocytes. These molecules are important for the sequestration of inflammatory neutrophils into the liver after an alcohol insult.
Specific aim 2 will examine the formation of oxygen-derived radicals, cytolytic proteases, proinflammatory cytokines and chemokines in the liver, which are considered to contribute to the induction of tissue injury in chronic alcoholics. Based on the results of specific aims 1 & 2, specific aim 3 examines the hypothesis that by neutralizing the deleterious effects of these metabolites and their sources (e. g. neutrophils and macrophages), hepatic injury will be attenuated or inhibited. This will be achieved by using free radical scavengers, protease inhibitors, monoclonal antibodies against adhesion molecules and liposome encapsulated dichloromethylene diphosphonate (which specifically targets Kupffer cells). This proposal is unique and novel, because it will use modern immunological and biotechnological approaches for the treatment of liver disease in chronic alcoholics. The use of free radical scavengers, liposomes and monoclonal antibodies in the immunotherapy of endotoxemia, cancer, ischemia-reperfusion and immunosuppression is gaining acceptance, and may also be applied to the treatment of tissue injury in the liver and other organs during chronic alcohol intoxication.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA010466-03
Application #
2682988
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1996-04-01
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
2000-03-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Physiology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112