Ethanol disrupts hepatic function with the eventual appearance of alcoholic liver disease (ALD). The characteristic pattern of liver injury in response to ethanol, progressing from fatty liver to inflammation and necrosis to fibrosis, is typical of the wound healing response of liver and other tissues to injury. Continued exposure to ethanol may disorder this """"""""wound healing"""""""" response. While a highly regulated secretion of inflammatory and fibrogenic cytokines is part of any wound healing process, the abnormal production of a variety of inflammatory and fibrogenic cytokines by Kupffer cells, the resident macrophage in the liver, is critical to the onset of ethanol-induced liver injury. In particular, increased expression of TNFalpha has been implicated in ethanol-induced liver injury. Clinical investigations of the therapeutic efficacy of anti-TNFalpha antibodies (e.g. Infliximab) to treat acute alcoholic steatohepatitis are under way. However, because TNFalpha is a critical component of the normal innate immune response, infectious disease is a primary concern during anti-TNFalpha therapy. Moreover, TNFalpha also plays a beneficial role in liver regeneration, essential to restoring hepatic function after injury. Therefore, therapeutic strategies to normalize, rather than eliminate, TNFalpha expression would be beneficial. We have recently discovered that increased activation of ERK1/2 and subsequent synthesis of Egr-1, a Zn-finger transcription factor, is critical for sustaining increased TNFalpha expression after chronic ethanol exposure in both Kupffer cells isolated from rats fed an ethanol containing diet, as well as in a macrophage cell line exposed to ethanol during culture. We hypothesize that increased Egr-1 expression is critical to the progression of ethanol-induced liver injury. Using both in vivo and cell culture models of chronic ethanol exposure, here we propose to 1) determine the mechanism for increased Egr-1 expression in macrophages after chronic ethanol, 2) determine the role of Egr-1 in expression of genes implicated in the development of ALD, 3) determine the in vivo effects of chronic ethanol on Egr-1 expression and, using egr-1 -/- mice, investigate the role of Egr-1 in the development of ethanol-induced liver injury. Understanding the mechanisms by which chronic ethanol increases Egr-1 expression will facilitate future studies to develop pharmacotherapeutic strategies to prevent and/or reverse ALD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013868-03
Application #
7032913
Study Section
Special Emphasis Panel (ZRG1-GMA-3 (02))
Program Officer
Guo, Qingbin
Project Start
2004-06-01
Project End
2006-07-15
Budget Start
2006-04-01
Budget End
2006-07-15
Support Year
3
Fiscal Year
2006
Total Cost
$130,595
Indirect Cost
Name
Case Western Reserve University
Department
Nutrition
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Roychowdhury, Sanjoy; McMullen, Megan R; Pisano, Sorana G et al. (2013) Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 57:1773-83
Roychowdhury, Sanjoy; Chiang, Dian J; Mandal, Palash et al. (2012) Inhibition of apoptosis protects mice from ethanol-mediated acceleration of early markers of CCl4 -induced fibrosis but not steatosis or inflammation. Alcohol Clin Exp Res 36:1139-47
Pritchard, Michele T; Cohen, Jessica I; Roychowdhury, Sanjoy et al. (2010) Early growth response-1 attenuates liver injury and promotes hepatoprotection after carbon tetrachloride exposure in mice. J Hepatol 53:655-62
Roychowdhury, Sanjoy; McMullen, Megan R; Pritchard, Michele T et al. (2009) Formation of gamma-ketoaldehyde-protein adducts during ethanol-induced liver injury in mice. Free Radic Biol Med 47:1526-38
Li, Wei; Laird, James M; Lu, Liang et al. (2009) Isolevuglandins covalently modify phosphatidylethanolamines in vivo: detection and quantitative analysis of hydroxylactam adducts. Free Radic Biol Med 47:1539-52
Park, Pil-Hoon; Huang, Honglian; McMullen, Megan R et al. (2008) Suppression of lipopolysaccharide-stimulated tumor necrosis factor-alpha production by adiponectin is mediated by transcriptional and post-transcriptional mechanisms. J Biol Chem 283:26850-8
Huang, Honglian; Park, Pil-Hoon; McMullen, Megan R et al. (2008) Mechanisms for the anti-inflammatory effects of adiponectin in macrophages. J Gastroenterol Hepatol 23 Suppl 1:S50-3
McMullen, Megan R; Pritchard, Michele T; Nagy, Laura E (2008) Isolation of Kupffer cells from rats fed chronic ethanol. Methods Mol Biol 447:199-212
Pritchard, Michele T; McMullen, Megan R; Medof, M Edward et al. (2008) Role of complement in ethanol-induced liver injury. Adv Exp Med Biol 632:175-86
Park, Pil-hoon; Huang, Honglian; McMullen, Megan R et al. (2008) Activation of cyclic-AMP response element binding protein contributes to adiponectin-stimulated interleukin-10 expression in RAW 264.7 macrophages. J Leukoc Biol 83:1258-66

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