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.
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