[2] Alternate techniques of ad libitum ethanol delivery, in which ethanol is incorporated into a liquid diet,[3] partially overcome a rodent’s natural aversion to alcohol and daily ethanol intake is sufficient to produce steatosis. Although liquid diet models are distinct improvements over drinking water models, liver

pathology is still limited predominantly to steatosis.[3] Another means to bypass aversion to ethanol is by enteral feeding by way of a surgically implanted intragastric tube,[4] which allows the researcher to achieve blood alcohol counts (BACs) that are much higher than ad libitum alcohol feeding. The main advantage of enteral feeding is that the pathology is more severe than in ad libitum models and better mimics early ALD in humans.[4] However, the technical demands of this protocol have limited the number of research JNK inhibitor groups that actively employ it. Although hepatic steatosis is generally considered an asymptomatic disease state, it sensitizes the liver to injury caused by a second insult.[5] For example, steatosis caused

by ethanol exposure is well known to enhance liver pathology induced by bolus injection of the bacterial cell wall product, lipopolysaccharide (LPS).[6] However, although circulating LPS levels are Gemcitabine cost elevated in both humans and in experimental animals consuming ethanol,[7, 8] these levels are much lower than observed after bolus injection in these models. Therefore, the relevance of the alcohol:LPS “2-hit” model to human ALD has been questioned.[9] LPS is not the only hit for which ethanol exposure enhances hepatotoxicity. Indeed, human studies have suggested that the risk of ALD increases in individuals who engage in binge episodes of drinking

on top of heavy daily consumption.[10] These data suggest that acute high-dose ethanol exposure itself can serve as the second “hit” on the background of chronic consumption. Gao and colleagues have “reverse-translated” these clinical observations into a mouse model of acute bolus ethanol exposure after chronic ad libitum exposure (i.e., the “NIAAA model”[11, 12]). This model employs 10 days ad libitum exposure, followed by an acute bolus gavage (Fig. 1); the latter dose regimen yields BACs of ∼400 mg/dL,[12] which is in the range that “professional” 5-Fluoracil order drinkers can attain.[13] Whereas neither the chronic nor the acute regimens cause major hepatic changes by themselves, their combination synergistically induces inflammatory liver damage[11, 12]; this model may also therefore represent human acute alcoholic hepatitis (AH). The results of the current study indicate that neutrophil chemoattraction plays a key role in the observed liver damage in this model.[14] Monocytes/macrophages appear to play a more dominant role in most rodent models of AH/ALD, whereas human AH has a strong neutrophil component.[15] Here, the production of neutrophil chemoattractants (e.g.