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Alcoholic liver disease (ALD) develops in approximately 20% of all alcoholics with a higher prevalence in females [1]. The development of fibrosis and cirrhosis is a complex process involving both parenchymal and non-parenchymal cells resident in the liver, as well as the recruitment of additional cell types to the liver in response to damage and inflammation [2]. Kupffer cells, the resident macrophages in the liver, are critical to the onset of ethanol-induced liver injury. Ablation of Kupffer cells prevents the development of fatty liver and inflammation, early events in the progression of ethanol-induced liver damage, in rats chronically exposed to ethanol via intragastric feeding [3]. Endotoxin (or lipopolysaccharide (LPS)), a component of the cell wall of gram-negative bacteria, is an important activator of Kupffer cells, stimulating the production of inflammatory and fibrogenic cytokines, as well as reactive oxygen species. LPS concentration is increased in the blood of alcoholics [4,5] and rats exposed to ethanol via intra-gastric infusion [6], probably due to impaired barrier function of the intestinal mucosa [7]). In a series of elegant experiments using transgenic animals from the laboratory of Ron Thurman, a working model for the development of alcoholic liver disease has been developed. This model proposes that increased exposure of Kupffer cells to LPS during chronic ethanol consumption results in increased production of inflammatory mediators, in particular TNF-alpha and reactive oxygen species, leading to the progression of fatty liver, inflammation and fibrosis, characteristic of ALD [7]. In addition to this increased exposure of Kupffer cells to LPS in response to ethanol, we and others have shown that chronic ethanol also sensitizes Kupffer cell responses to LPS [8,9]. We hypothesize that increased sensitivity to LPS stimulation after chronic ethanol exposure likely contributes to the progression of liver injury.  Role of TNF-alpha in the progression of alcoholic liver disease TNF-alpha is thought to play a particularly critical role in the pathogenesis of ALD. TNF-alpha is one of the principal mediators of the inflammatory response in mammals, transducing differential signals that regulate cellular activation and proliferation, cytotoxicity and apoptosis [10,11] In addition to its role in acute septic shock, TNF-alpha has been implicated in the pathogenesis of a wide variety of inflammatory diseases [11,12,14] as well as in the progression of alcoholic liver disease [7,15] The role of TNF-alpha in the development of ethanol-induced liver injury has been well characterized in animal models [7,15]  Production of TNF-alpha is one of the earliest responses of the liver to injury [15]. Circulating TNF-alpha is increased in the blood of alcoholics and in animals chronically exposed to ethanol [16,17]. Antibiotic treatment decreases TNF-alpha expression and ethanol-induced liver injury in rats exposed to ethanol via intra-gastric infusion [7], suggesting that increased TNF-alpha after ethanol exposure is due, at least in part, to increased exposure to LPS. In addition to increasing LPS exposure, chronic ethanol also increases sensitivity to LPS. For example, long-term ethanol consumption increases the susceptibility of rats to endotoxin-induced liver injury [8,18]. Moreover, we have shown that LPS-stimulated TNF-alpha secretion is increased in Kupffer cells isolated from rats fed ethanol in their diet for 4 weeks compared to pair-fed controls [9,19,20].

comparative hepatology

Lipopolysaccharide-mediated signal transduction: Stabilization of TNF-alpha mRNA contributes to increased lipopolysaccharide-stimulated TNF-alpha production by Kupffer cells after chronic ethanol feeding.