The morbidity and mortality resulting from alcohol-related diseases impose a substantive cost to society globally. To minimize the financial burden on society and improve the quality of life for individuals suffering from the ill effects of alcohol abuse, researchers in the alcohol field are focused on understanding the mechanisms by which alcohol-related diseases develop and progress. Since ethical concerns and inherent difficulties limit the amount of alcohol abuse research that can be performed in humans, most is performed in laboratory animals. This article summarizes the various laboratory models of alcohol abuse that are currently available and are used to study the mechanisms by which alcohol abuse induces organ damage and immune defects. The strengths and weaknesses of each of the models are discussed. Integrated into the review are the presentations that were made in the symposium “Methods of Ethanol Application in Alcohol Model – How Long is Long Enough” at the joint 2008 Research Society on Alcoholism (RSA) and International Society for Biomedical Research on Alcoholism (ISBRA) meeting, Washington, DC, emphasizing the importance not only of selecting the most appropriate laboratory alcohol model to address the specific goals of a project but also of ensuring that the findings can be extrapolated to alcohol-induced diseases in humans.

Alcohol is recognized as a direct hepatotoxin, but the precise molecular pathways that are important for the initiation and progression of alcohol-induced tissue injury are not completely understood. The current understanding of alcohol toxicity to organs suggests that alcohol initiates injury by generation of oxidative and nonoxidative ethanol metabolites and via translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. With continuing alcohol abuse, the injury progresses through impairment of tissue regeneration and extracellular matrix (ECM) turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, the predominant being stellate cells, macrophages, and parenchymal cells. In response to alcohol, growth factors and cytokines activate many signaling cascades that regulate fibrogenesis. This mini-review brings together research focusing on the underlying mechanisms of alcohol-mediated injury in a number of organs. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, susceptibility to infection, ECM turnover and fibrogenesis in the liver, pancreas, and lung triggered by alcohol abuse.

Previous studies have shown that alcohol (EtOH) intoxication impairs lung immunity by affecting cytokines pivotal to the inflammatory process. The objective of this study was to test the hypothesis that acute alcohol intoxication impairs lung innate immunity by down-regulating the expression of pro-inflammatory mediators while simultaneously up-regulating anti-inflammatory mediators. EtOH was administered to the mice 0.5 h prior to an intra-tracheal injection of E. coli lipopolysaccharide (LPS). The animals were killed either 4 or 24 h after LPS to recover plasma, lungs and bronchoalveolar lavage fluid. Lung inflammatory cytokines TNF-α, IL-1β, IL-6, MIF, IL-10, TGF-β and receptors for TNF-α, IL-1β, IL-6 and TGF-β as well as gp130 and corticosterone levels were evaluated at mRNA and protein level. While the mRNA expression and the soluble TNF-Rp55 levels were significantly up-regulated by EtOH, LPS-induced TNF-α activity, TNF-Rp55 mRNA expression and soluble TNF-Rp55 levels were significantly suppressed. The LPS-induced expression of IL-1β, IL-6, MIF, gp130, and receptors IL-1RI, IL-1RII and IL-6Rα were also significantly impaired by EtOH. EtOH increased significantly basal IL-10 activity at 3 h, which continued to remain elevated even at 24 h. The EtOH effect on IL-10 activity persisted even in LPS-challenged mice. EtOH and LPS augmented lung corticosterone levels independently of each other. EtOH suppressed up-regulation of TGF-β1 mRNA expression by LPS and blocked completely LPSinduced TGF-β1 secretion. In conclusion, the data suggest that the suppression of acute lung inflammation by EtOH intoxication is largely due to impairment by EtOH of pro-inflammatory cytokine signaling at the levels of cytokine expression and secretion as well as receptor expression and soluble receptor activity. The augmentation by EtOH of anti-inflammatory mediators' secretion most likely shifts the cytokine balance in the anti-inflammatory direction.

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