This proposal is an extension (as an R01) of the currently """"""""FIRST award""""""""-funded project, entitled """"""""The role of the liver in the immunodeficiency of alcoholics (R29 AA08846). Studies supported by this grant demonstrated that the effect of alcohol on the liver is a paradox. Based on these observations, the overall objective of this proposal is to examine the mechanisms by which acute or chronic alcohol intoxication regulates some aspects of the hepatic immune system that contribute to the development of hepatic injury and immunosuppression. Hypothesis 1: Chronic alcohol intoxication induces endotoxin influx in the circulation which in turn stimulates hepatic macrophages to produce macrophage inflammatory protein-2(MIP2), a potent stimulus for PMN chemotaxis, superoxide release and hepatotoxicity. Consequently, there is enhanced expression of adhesion molecules on leukocytes and hepatic cells, which can lead to increased migration of inflammatory PMNs (neutrophils) in the liver, resulting in hepatic injury.
Specific aim 1 : To determine the effect of chronic alcohol intoxication on serum endotoxin, MIP2 production in vivo and in vitro, adhesion molecule expression on peripheral PMNs and hepatic cells, and hepatotoxicity and to determine LPS clearance. Hypothesis 2: Alcohol withdrawal, following an acute alcohol binge exacerbates the toxic effects of endotoxic shock.
Specific aim 2 : To determine the effect of endotoxemia during alcohol withdrawal on TNF and MIP2 production, hepatic migration of PMNs, and spontaneous superoxide anion production by hepatic non-parenchymal cells. The effect of alcohol withdrawal on LPS-induced mortality and hepatic injury will be studied. Hypothesis 3: Immunosuppression is more frequently encountered among chronic alcoholics, which may be partially due to the down regulation of antigen or ligand-induced respiratory burst.
Specific aim 3 : To study the effect of prolonged consumption of alcohol on opsonized-Escherichia coli-induced production of extracellular superoxide anion and intracellular H2O2 and Fc receptor expression on Kupffer cells. The microbicidal activity of these cells or, lack thereof, will be tested by using viable E. Coli as target cells. This proposal is unique and novel because it will elucidate the role of a newly discovered chemokine, macrophage inflammatory protein-2 (MIP2) on the induction of alcohol-associated liver injury. The proposed research also includes studies on the role of alcohol-mediated regulation of Fc receptor expression and respiratory burst in Kupffer cells. Results that will be generated from this competitive renewal are expected to provide new and exciting information that may have an important application for the immunotherapy of alcoholics whose livers are further compromised by trauma or infection.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA008846-07
Application #
2871406
Study Section
Special Emphasis Panel (ZRG4-ALTX-1 (03))
Program Officer
Isaki, Leslie
Project Start
1991-08-01
Project End
2001-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
7
Fiscal Year
1999
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
Bautista, Abraham P (2002) Chronic alcohol intoxication primes Kupffer cells and endothelial cells for enhanced CC-chemokine production and concomitantly suppresses phagocytosis and chemotaxis. Front Biosci 7:a117-25
Bautista, Abraham P; Wang, Enze (2002) Acute ethanol administration downregulates human immunodeficiency virus-1 glycoprotein 120-induced KC and RANTES production by murine Kupffer cells and splenocytes. Life Sci 71:371-82
Prakash, Om; Mason, Andrew; Luftig, Ronald B et al. (2002) Hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) infections in alcoholics. Front Biosci 7:e286-300
Bautista, Abraham P (2002) Acute ethanol binge followed by withdrawal regulates production of reactive oxygen species and cytokine-induced neutrophil chemoattractant and liver injury during reperfusion after hepatic ischemia. Antioxid Redox Signal 4:721-31
Bautista, A P (2001) Acute alcohol intoxication and endotoxemia desensitize HIV-1 gp120-induced CC-chemokine production by Kupffer cells. Life Sci 68:1939-49
Bautista, A P; Wang, E (2001) Chronic ethanol intoxication enhances the production of cytokine-induced neutrophil chemoattractant and macrophage inflammatory protein-2 by hepatocytes after human immunodeficiency virus-1 glycoprotein 120 vaccination. Alcohol 24:35-44
Bautista, A P (2000) Impact of alcohol on the ability of Kupffer cells to produce chemokines and its role in alcoholic liver disease. J Gastroenterol Hepatol 15:349-56
Bukara, M; Bautista, A P (2000) Acute alcohol intoxication and gadolinium chloride attenuate endotoxin-induced release of CC chemokines in the rat. Alcohol 20:193-203