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      Alcoholic liver disease: Utility of animal models

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          Abstract

          Alcoholic liver disease (ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.

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          Most cited references91

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          Of mice and not men: differences between mouse and human immunology.

          Mice are the experimental tool of choice for the majority of immunologists and the study of their immune responses has yielded tremendous insight into the workings of the human immune system. However, as 65 million years of evolution might suggest, there are significant differences. Here we outline known discrepancies in both innate and adaptive immunity, including: balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets, the B cell (BLNK, Btk, and lambda5) and T cell (ZAP70 and common gamma-chain) signaling pathway components, Thy-1, gammadelta T cells, cytokines and cytokine receptors, Th1/Th2 differentiation, costimulatory molecule expression and function, Ag-presenting function of endothelial cells, and chemokine and chemokine receptor expression. We also provide examples, such as multiple sclerosis and delayed-type hypersensitivity, where complex multicomponent processes differ. Such differences should be taken into account when using mice as preclinical models of human disease.
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            Mouse model of chronic and binge ethanol feeding (the NIAAA model).

            Chronic alcohol consumption is a leading cause of chronic liver disease worldwide, leading to cirrhosis and hepatocellular carcinoma. Currently, the most widely used model for alcoholic liver injury is ad libitum feeding with the Lieber-DeCarli liquid diet containing ethanol for 4-6 weeks; however, this model, without the addition of a secondary insult, only induces mild steatosis, slight elevation of serum alanine transaminase (ALT) and little or no inflammation. Here we describe a simple mouse model of alcoholic liver injury by chronic ethanol feeding (10-d ad libitum oral feeding with the Lieber-DeCarli ethanol liquid diet) plus a single binge ethanol feeding. This protocol for chronic-plus-single-binge ethanol feeding synergistically induces liver injury, inflammation and fatty liver, which mimics acute-on-chronic alcoholic liver injury in patients. This feeding protocol can also be extended to chronic feeding for longer periods of time up to 8 weeks plus single or multiple binges. Chronic-binge ethanol feeding leads to high blood alcohol levels; thus, this simple model will be very useful for the study of alcoholic liver disease (ALD) and of other organs damaged by alcohol consumption.
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              Alcohol metabolism.

              This article describes the pathways and factors that modulate blood alcohol levels and metabolism and describes how the body disposes of alcohol. The various factors that play a role in the distribution of alcohol in the body, influence the absorption of alcohol, and contribute to first-pass metabolism of alcohol are described. Most alcohol is oxidized in the liver, and general principles and overall mechanisms for alcohol oxidation are summarized. The kinetics of alcohol elimination in-vivo and the various genetic and environmental factors that can modify the rate of alcohol metabolism are discussed. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                World J Gastroenterol
                World J. Gastroenterol
                WJG
                World Journal of Gastroenterology
                Baishideng Publishing Group Inc
                1007-9327
                2219-2840
                7 December 2018
                7 December 2018
                : 24
                : 45
                : 5063-5075
                Affiliations
                Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
                Yulia A Nevzovova, Francisco Javier Cubero, 12 de Octubre Health Research Institute (imas12), Madrid 28041, Spain
                Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
                Yulia A Nevzovova, Francisco Javier Cubero, 12 de Octubre Health Research Institute (imas12), Madrid 28041, Spain
                Institute for Bioengineering (IBioE), School of Engineering, Faraday Building, The University of Edinburgh, Edinburgh EH9 3 JL, Scotland, United Kingdom
                Department of Human Anatomy and Embryology, Complutense University School of Medicine, Madrid 28040, Spain
                Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, San Juan de Alicante 03550, Spain
                Department of Cell Biology, Complutense University School of Medicine, Madrid 28040, Spain
                Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
                Yulia A Nevzovova, Francisco Javier Cubero, 12 de Octubre Health Research Institute (imas12), Madrid 28041, Spain
                Department of Genetics, Physiology and Microbiology, Faculty of Biology, Universidad Complutense, Madrid 28040, Spain
                Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52062, Germany
                Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain. fcubero@ 123456ucm.es
                Author notes

                Author contributions: Lamas-Paz A and Hao F equally contributed to the manuscript writing and figure design; Nelson LJ, Vázquez MT, Canals S, Gómez del Moral M and Martínez-Naves E critiqued the manuscript, checked English language and provided fundamental guidance. Nevzorova YA and Cubero FJ outlined and corrected the review and provided guidance.

                Supported by the MINECO Retos, No. SAF2016-78711 and SAF2017-87919R; EXOHEP-CM, No. S2017/BMD-3727; the AMMF Cholangiocarcinoma Charity, No. 2018/117; the COST Action, No. CA17112; Ramón y Cajal, No. RYC-2014-15242 and No. RYC-2015-17438; grant of ERAB, No. EA 14/18; Gilead Liver Research Scholar 2018, No. 44/2018; Ministerio de Sanidad, Servicios Sociales e Igualdad, No. 2017I065; and the UCM group “Lymphocyte Immunobiology”, No. 920631 (imas12-associated, Ref. IBL-6). German Research Foundation (SFB/TRR57/P04 and DFG NE 2128/2-1); Interdisciplinary Center for Clinical Research from the Faculty of Medicine at RWTH Aachen University (IZKF/E8-2) .

                Correspondence author to: Francisco Javier Cubero, BSc, MSc, PhD, Assistant Professor, Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, c/Doctor Severo Ochoa 9, Madrid 28040, Spain. fcubero@ 123456ucm.es

                Telephone: +34-91-3941385 Fax: +34-91-394164

                Article
                jWJG.v24.i45.pg5063
                10.3748/wjg.v24.i45.5063
                6288648
                30568384
                19dc8d8c-8830-4a64-a97d-24221a64847b
                ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.

                This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                : 19 October 2018
                : 8 November 2018
                : 9 November 2018
                Categories
                Review

                steatohepatitis,cirrhosis,hepatocellular carcinoma,alcoholic liver disease,reactive oxygen species

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