Alcoholic liver disease (ALD) is a serious consequence of alcohol abuse and results in a great deal of morbidity and mortality in the United States. The mechanisms that lead to ALD are poorly understood, and it is not known what factors are involved in the susceptibility for the development of ALD. The prevailing opinion is that some factor initiates an inflammatory response in the liver that is uncontrolled and ultimately results in the characteristic fibrosis associated with this process. Data from this laboratory have shown that a condition that resembles the sequence of events in ALD can be initiated in ethanol (ETOH)-fed C57Bl/6 mice after activation of T-lymphocytes by specific antigen or concanavalin A. These activation stimuli induce steatosis and hepatitis only in ETOH-fed mice, which ultimately result in liver damage evidenced by elevated serum levels of ALT and AST. These data support our suggestion that at least one factor involved in initiation and development of ALD is a specific immune response in the liver. To test this hypothesis we propose to use these murine models of ALD and a model of viral hepatitis to define the mechanisms responsible for this immune - mediated liver damage. It is our specific hypothesis that initiation of the inflammatory process is the result of specific T cell-mediated killing, either through direct cellular cytotoxicity or through the production of cytotoxic cytokines of the infected hepatocyte. Further, we hypothesize that corticosteroid production associated with ETOH consumption has a twofold effect in this system. First, the immune response is suppressed by corticosteroids to inhibit the ability to control the replication of the infectious agents, results in more inflammation. Second, corticosteroids sensitizes hepatocytes to enhance destruction of these cells by either direct T-cell-mediated lysis or lysis mediated by inflammatory cytokines such as tumor necrosis factor. The proposed research will also define the specific cells that initiate or mediate liver damage as well as the role of the inflammatory response and inflammatory cytokines in these models of experimental ALD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012450-02
Application #
6168519
Study Section
Special Emphasis Panel (ZRG1-ALTX-1 (03))
Program Officer
Lucas, Diane
Project Start
1999-04-01
Project End
2003-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
2
Fiscal Year
2000
Total Cost
$166,238
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Gurung, Prajwal; Young, Betty M; Coleman, Ruth A et al. (2009) Chronic ethanol induces inhibition of antigen-specific CD8+ but not CD4+ immunodominant T cell responses following Listeria monocytogenes inoculation. J Leukoc Biol 85:34-43
Ness, Kristin J; Fan, Ji; Wilke, Werner W et al. (2008) Chronic ethanol consumption decreases murine Langerhans cell numbers and delays migration of Langerhans cells as well as dermal dendritic cells. Alcohol Clin Exp Res 32:657-68
Edsen-Moore, Michelle R; Fan, Ji; Ness, Kristin J et al. (2008) Effects of chronic ethanol feeding on murine dendritic cell numbers, turnover rate, and dendropoiesis. Alcohol Clin Exp Res 32:1309-20
Cook, Robert T; Schlueter, Annette J; Coleman, Ruth A et al. (2007) Thymocytes, pre-B cells, and organ changes in a mouse model of chronic ethanol ingestion--absence of subset-specific glucocorticoid-induced immune cell loss. Alcohol Clin Exp Res 31:1746-58
Jerrells, Thomas R; Pavlik, Jacqueline A; DeVasure, Jane et al. (2007) Association of chronic alcohol consumption and increased susceptibility to and pathogenic effects of pulmonary infection with respiratory syncytial virus in mice. Alcohol 41:357-69
Sosa, Laura; Vidlak, Debbie; Strachota, Jennifer M et al. (2005) Rescue of in vivo FAS-induced apoptosis of hepatocytes by corticosteroids either associated with alcohol consumption by mice or provided exogenously. Int Immunopharmacol 5:301-14
Kovacs, Elizabeth J; Jerrells, Thomas R; Alcohol and Immunology Research Interest Group (2004) Alcohol and immunology: introduction to and summary of the 2003 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 33:171-4
Nagy, Laura E; Lakshman, M Raj; Casey, Carol A et al. (2002) Ethanol and membrane protein trafficking: diverse mechanisms of ethanol action. Alcohol Clin Exp Res 26:287-93
Jerrells, Thomas R (2002) Association of alcohol consumption and exaggerated immunopathologic effects in the liver induced by infectious organism. Front Biosci 7:d1487-93
Jerrells, Thomas R (2002) Role of activated CD8+ T cells in the initiation and continuation of hepatic damage. Alcohol 27:47-52

Showing the most recent 10 out of 14 publications