慢性酒精喂养加急性酒精灌胃的酒精性肝病小鼠模型（NIAAA模型或Gao—Binge模型）

酒精性肝病是进展期肝病非常重要的原因之一,目前对其发病机制及治疗靶点的研究主要基于动物模型,因此建立一个与人类酒精性肝病类似的模型就至关重要。过去建立的一些酒精性肝病动物模型,或者肝损伤轻微,或者难于操作,近期由美国国立卫生院酒精滥用与酒精中毒研究所肝病研究室建立的新模型,即慢性酒精喂养加急性酒精灌胃的酒精性肝病小鼠模（NIAAA模型或Gao—Binge模型）,更接近于人类的饮酒方式,肝损伤更明显,而且容易操作,费用低和时间短。     

Fibrogenesis in alcoholic liver disease

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. In developed countries, ALD is a major cause of end-stage liver disease that requires transplantation. The spectrum of ALD includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Alcohol abstinence is the most effective therapy for ALD. However, targeted therapies are urgently needed for patients with severe ALD (i.e., alcoholic hepatitis) or those who do not abstain from alcohol. The lack of studies and the availability of animal models that do not reflect all the features of this disease in humans inhibit the development of new drugs for ALD. In ALD-associated fibrosis, hepatic stellate cells are the principal cell type responsible for extracellular matrix production. Although the mechanisms underlying fibrosis in ALD are largely similar to those observed in other chronic liver diseases, oxidative stress, methionine metabolism abnormalities, hepatocyte apoptosis, and endotoxin lipopolysaccharides that activate Kupffer cells may play unique roles in disease-related fibrogenesis. Lipogenesis during the early stages of ALD has recently been implicated as a risk factor for the progression of cirrhosis. Other topics include osteopontin, interleukin-1 signaling, and genetic polymorphism. In this review, we discuss the basic pathogenesis of ALD and focus on liver fibrogenesis.     

Animal models of alcoholic liver disease

The risk of alcohol-induced liver disease (ALD) increases dose- and time-dependently with consumption of alcohol. The progression of the disease is well characterized; however, although the progression of alcohol-induced liver injury is well characterized, there is no universally-accepted therapy available to halt or reverse this process in humans. With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of this disease, rational targeted therapy can be developed to treat or prevent it in the clinics. Several models for experimental ALD exist, including non-human primates, micropigs and rodents. However, most researchers employ rodent models of ALD. Furthermore, the advent of genetically modified strains of rodents (e.g. 'knockout' mice) has increased the specificity of the hypotheses that can be directly tested. Based on these models systems, several plausible hypotheses to explain the mechanism(s) by which alcohol leads to liver damage have been proposed, including consequences of alcohol metabolism, oxidative/nitrosative stress, altered inflammatory responses, and increased sensitivity to cytotoxic stimuli. These studies have also identified candidate genes for polymorphism studies to explain potential increased genetic risk in some individuals. However, despite significant advances in our understanding of the mechanisms by which ALD develops based on studies with these models, this work has yet to translate to a viable therapy for ALD in the clinics. This talk will also discuss potential reasons for these limitations to date and suggest future prospects to improve the translational utility of modeling ALD.     

自身免疫性肝炎动物模型研究进展

近年来,自身免疫性肝炎(AIH)的检出率逐渐上升,日益引起人们的关注。虽然AIH的自身抗体已经明确,但其病因和引起肝细胞损伤的机制却仍未完全阐明,主要原因之一就是缺乏理想的能够模拟AIH慢性进展性免疫损伤过程的动物模型。大多数AIH动物模型只能引起短暂的肝损伤,且需要复杂的诱导方法。本文对几种经典和目前较新的AIH动物模型及其优缺点作一总结。     

Animal Models in Alcoholic Pancreatitis — What Can We Learn?

Although the majority of patients with chronic pancreatitis present a history of excessive alcohol consumption, the pathophysiology underlying chronic alcoholic pancreatitis remains poorly defined. Since experimental animal models represent helpful tools in understanding human disease, numerous laboratory studies have been designed to study the effects of alcohol on the pancreas. In the present article we summarize the existing animal models that have been used to investigate the effects of acute and chronic alcohol application on the development of morphological alterations and pancreatic injury. Despite considerable experimental effort, acute or chronic ethanol feeding alone failed to cause acute or chronic pancreatitis in animals. However, ethanol-feeding and the combination with other procedures has demonstrated several mechanisms that play a role in ethanol-induced pancreatic injury. Among these ethanolinduced alterations and mechanisms are the reduction of pancreatic blood-flow and microcirculation, damaging effects of ethanol metabolites, increased pancreatic acinar cell expression of digestive and lysosomal enzymes, increased glandular enzyme content, additional nutritional factors, pancreatic duct obstruction, and limitations of pancreatic regeneration. Although no satisfactory animal model for alcoholic pancreatitis has been developed, these animal models have provided insights in several factors that predispose the pancreas to development of pancreatic injury and contribute to alcoholic pancreatitis.     

Experimental models of metabolic and alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a multi-systemic disease that is considered the hepatic manifestation of metabolic syndrome (MetS). Because alcohol consumption in NAFLD patients is common, there is a significant overlap in the pathogenesis of NAFLD and alcoholic liver disease (ALD). Indeed, MetS also significantly contributes to liver injury in ALD patients. This “syndrome of metabolic and alcoholic steatohepatitis” (SMASH) is thus expected to be a more prevalent presentation in liver patients, as the obesity epidemic continues. Several pre-clinical experimental models that couple alcohol consumption with NAFLD-inducing diet or genetic obesity have been developed to better understand the pathogenic mechanisms of SMASH. These models indicate that concomitant MetS and alcohol contribute to lipid dysregulation, oxidative stress, and the induction of innate immune response. There are significant limitations in the applicability of these models to human disease, such as the ability to induce advanced liver injury or replicate patterns in human food/alcohol consumption. Thus, there remains a need to develop models that accurately replicate patterns of obesogenic diet and alcohol consumption in SMASH patients.     

Animal Models for Fibrotic Liver Diseases: What We Have,What We Need,and What Is under Development

Liver fibrosis is part of the wound-healing response to liver damage of various origins and represents a major health problem. Although our understanding of the pathogenesis of liver fibrosis has grown considerably over the last 20 years, effective antifibrotic therapies are still lacking. The use of animal models is crucial for determining mechanisms underlying initiation, progression, and resolution of fibrosis and for developing novel therapies. To date, no animal model can recapitulate all the hepatic and extra-hepatic features of liver disease. In this review, we will discuss the current rodent models of liver injuries. We will then focus on the available ways to target specifically particular compounds of fibrogenesis and on the new models of liver diseases like the humanized liver mouse model.     

Novel therapeutic avenues for the study of chronic liver disease and regeneration: The foundation of the Iberoamerican Consortium for the study of liver Cirrhosis

Unfortunately, there is a gap of understanding in the pathophysiology of chronic liver disease due to the lack of experimental models that exactly mimic the human disease. Additionally, the diagnosis of patients is very poor due to the lack of biomarkers than can detect the disease in early stages. Thus, it is of utmost interest the generation of a multidisciplinary consortium from different countries with a direct translation. The present reports the meeting of the 2021 Iberoamerican Consortium for the study of liver Cirrhosis, held online, in October 2021. The meeting, was focused on the recent advancements in the field of chronic liver disease and cirrhosis with a specific focus on cell pathobiology and liver regeneration, molecular and cellular targets involved in non-alcoholic hepatic steatohepatitis, alcoholic liver disease (ALD), both ALD and western diet, and end-stage liver cirrhosis and hepatocellular carcinoma. In addition, the meeting highlighted recent advances in targeted novel technology (-omics) and opening therapeutic avenues in this field of research.     

Adipose tissue-liver axis in alcoholic liver disease

Alcoholic liver disease(ALD) remains an important health problem worldwide. The disease spectrum is featured by early steatosis, steatohepatitis(steatosis with inflammatory cells infiltration and necrosis), with some individuals ultimately progressing to fibrosis/cirrhosis. Although the disease progression is well characterized, no effective therapies are currently available for the treatment in humans. The mechanisms underlying the initiation and progression of ALD are multifactorial and complex. Emerging evidence supports that adipose tissue dysfunction contributes to the pathogenesis of ALD. In the first part of this review, we discuss the mechanisms whereby chronic alcohol exposure contributed to adipose tissue dysfunction, including cell death, inflammation and insulin resistance. It has been long known that aberrant hepatic methionine metabolism is a major metabolic abnormality induced by chronic alcohol exposure and plays an etiological role in the pathogenesis of ALD. The recent studies in our group documented the similar metabolic effect of chronic alcohol drinking on methionine in adipose tissue. In the second part of this review, we also briefly discuss the recent research progress in the field with a focus on how abnormal methionine metabolism in adipose tissue contributes to adipose tissue dysfunction and liver damage.     

Oxidants and antioxidants in alcohol-induced liver disease

Although there are numerous experimental data indicating that oxidative stress plays a role in the initiation and progression of alcohol-induced liver disease (ALD), this work has yet to translate into an accepted antioxidant therapy for ALD in humans. With a better understanding of the mechanisms by which oxidative stress leads to liver damage during alcohol exposure, therapies that are more targeted at the cellular/molecular level may be applied in the clinic with potentially greater success. This article discusses the general concepts of oxidative stress and how it relates to current hypotheses in alcohol-induced liver injury, as well as lists several key questions that remain to be addressed in this field: (1) Which prooxidants are involved in ALD? (2) What are the sources of prooxidants in the liver during alcohol exposure? (3) How are oxidants involved in alcohol-induced liver injury? (4) Can a rational and effective antioxidant therapy against ALD be developed?     

Alcoholic liver disease

Alcohol use disorders affect millions of individuals worldwide.Alcohol consumption is directly associated with liver disease mortality and accounts for elevated social and economic costs.Alcoholic liver disease(ALD) may take the form of acute involvement(alcoholic hepatitis)or chronic liver disease(steatosis,steatohepatitis,fibrosis and cirrhosis).The severity and prognosis of alcohol-induced liver disease depends on the amount,pattern and duration of alcohol consumption,as well as on the presence of liver inflammation,diet,nutritional status and genetic predisposition of an individual.While steatosis is an almost completely benign disease,liver cirrhosis is associated with marked morbidity,mortal-ity and life expectancy shortening.The median survival of patients with advanced cirrhosis is 1-2 years.Se-vere acute alcoholic hepatitis(AH)is associated with mortality as high as 50%.It has been managed with corticoids,pentoxifylline and enteral nutrition,although evidence based data are still conflicting.Some author suggest that pentoxifylline could be a better first-line treatment in patients with severe AH.Absolute abstinence is a basic condition for any treatment of acute or chronic ALD,the other therapeutical procedure being of a supportive nature and questionable significance.Acamprosate appears to be an effective treatment strategy for supporting continuous abstinence in alco-hol dependent patients.Patients with advanced liver cirrhosis who demonstrably abstain can be considered for liver transplantation,which leads to a markedly pro-longed life expectancy.The crucial step in ALD preven-tion is in the prevention of alcohol abuse,whereas the prevention of liver injury in active alcohol abusers is not clinically applicable.     

Dietary supplementation in patients with alcoholic liver disease：a review on current evidence

BACKGROUND: Alcoholic liver disease (ALD) is one of the main causes of liver disease worldwide. Although the patho-genesis of ALD has not yet been well elucidated, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxy-gen species play a pivotal role in the clinical and pathological spectrum of the disease. This review summarizes the existing evidences on dietary supplements considered to have antioxi-dant, and/or anti-inlfammatory properties, and their role in the management of ALD and the proposed mechanisms.
DATA SOURCES: The present study reviewed all studies pub-lished in PubMed, ScienceDirect and Scopus, from 1959 to 2015, indicating the role of different dietary supplementation in attenuation of many pathophysiological processes involved in development and progression of ALD. Full-texts of citations were used except for those that were published in languages other than English.
RESULTS: Signiifcant progress has been made to understand the key events and molecular players for the onset and pro-gression of ALD from both experimental and clinical studies;however, there is no successful treatment currently available. The present review discussed the role of a variety of dietary supplements (e.g. vitamin A, carotenoids, vitamins B3, C and E, in addition to antioxidants and anti-inlfammatory agents) in treating ALD. It has been shown that supplementation with some carotenoids, vitamin B3, vitamin C, silymarin, curcumin, probiotics, zinc, S-adenosylmethionine and garlic may have potential beneifcial effects in animal models of ALD; however, the number of clinical studies is very limited. In addition, sup-plementation should be accompanied with alcohol cessation.
CONCLUSIONS: Since oxidative stress and inlfammation are involved in the pathogenesis of ALD, dietary supplements that can modulate these pathologies could be useful in the treat-ment of ALD. In addition to alcohol cessation, these supple-ments have shown beneifcial effects on animal models of ALD. Clinical trials are needed to validate the beneifciary role of these supplements in patients with ALD.     

Hepatic encephalopathy:Lessons from preclinical studies

Hepatic encephalopathy(HE) is a major complication that is closely related to the progression of end-stage liver disease.Metabolic changes in advanced liver failure can promote cognition impairment,attention deficits and motor dysfunction that may result in coma and death.HE can be subdivided according to the type of hepatic injury,namely,type A,which results from acute liver failure,type B,which is associated with a portosystemic shunting without intrinsic liver disease,and type C,which is due to chronic liver disease.Several studies have investigated the pathogenesis of the disease,and most of the mechanisms have been explored using animal models.This article aimed to review the use of preclinical models to investigate HE.The most used animal species are rats and mice.Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications,whereas models of types B and C HE are generally surgically induced lesions in liver tissue,which evolve to hepatic cirrhosis.Preclinical models have allowed the comprehension of the pathways related to HE.     

Stem Cell Origins and Animal Models of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a common malignant tumor that almost always occurs within a preexisting background of chronic liver disease and cirrhosis. Currently, medical therapy is not effective in treating most HCC, and the only hope of cure is either resection or liver transplantation. A small minority of patients is eligible for these therapies, which entail major morbidity at the very least. In spite of immense scientific advances during the past 3 decades, patient survival has improved very little. In order to reduce morbidity and mortality from HCC, improvements in early diagnosis and development of novel local and systemic therapies for advanced disease are essential, in addition to efforts geared towards primary prevention. Studies with experimental animal models that closely mimic human disease are very valuable in understanding physiological, cellular and molecular mechanisms underlying the disease. Furthermore, appropriate animal models have the potential to increase our understanding of the effects of image-guided minimally invasive therapies and thereby help to improve such therapies. In this review, we examine the evidence for stem cell origins of such tumors, critically evaluate existing models and reflect on how to develop new models for minimally invasive, image-guided treatment of HCC.     

Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple hepatic steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. Although most subjects with excessive alcohol or food intake experience simple hepatic steatosis, a small percentage of individuals will develop progressive liver disease. Notably, both ALD and NAFLD are frequently accompanied by extrahepatic complications, including cardiovascular disease and malignancy. The survival of patients with ALD and NAFLD depends on various disease-associated conditions. This review delineates the clinical characteristics and outcomes of patients with ALD and NAFLD by comparing their epidemiology, the factors associated with disease susceptibility and progression, and the predictors and characteristics of outcomes. A comprehensive understanding of the characteristics and outcomes of ALD and NAFLD is imperative in the management of these chronic liver diseases.     

酒精性肝病与氧化应激

酒精性肝病(ALD)是威胁人类健康的重大疾病之一,其发病机制错综复杂。氧化应激性肝损害在其中占有至关重要的地位,如何系统的认识机体的氧化与抗氧化系统在ALD发生发展过程中所扮演的角色,对ALD的防治工作具有一定的指导意义。     

Hepatic 31P MRS in rat models of chronic liver disease: assessing the extent and progression of disease

BACKGROUND: Hepatic adenosine triphosphate (ATP) levels are an accurate reflection of functioning hepatic mass following surgical resections and acute liver injury. OBJECTIVE: To determine whether hepatic ATP levels can serve as a non-invasive means of documenting progression of chronic liver disease to cirrhosis. METHODS: In vivo phosphorus-31 magnetic resonance spectroscopy ((31)P MRS) was performed in three animal models of chronic liver disease. Sixty six adult Sprague- Dawley rats were subjected to either thioacetamide, carbon tetrachloride (CCl(4)), or common bile duct ligation (CBDL) to induce liver disease (n=35, 21, and 10, respectively). Serial MRS examinations, blood samples, and liver biopsies (when appropriate) were obtained throughout and/or on completion of the study. RESULTS: Over the course of the chronic liver disease, a progressive decrease in hepatic ATP levels was consistently observed in each model. The findings were most striking when end stage liver disease (cirrhosis) was established. The reduction in hepatic ATP levels correlated with significant changes in serum albumin concentrations (CCl(4) and CBDL models) and the extent of hepatocyte loss seen histologically (all models). CONCLUSION: The results of this study indicate that during progression of chronic liver disease to cirrhosis, there is a progressive reduction in hepatic ATP levels. In addition, changes in hepatic ATP levels correlate with changes in liver function and histology. Thus hepatic (31)P MRS provides a non-invasive means of documenting the severity and progression of parenchymal and cholestatic models of chronic liver disease in rats.     

Pathogenesis of alcoholic liver disease

Alcoholic liver disease (ALD) has become one of the most critical health problems in many countries, including Japan. Liver injury in ALD ranges from steatosis and steatohepatitis to fibrosis, cirrhosis, and hepatocellular carcinoma. Many factors are thought to contribute to the development and progression of ALD, particularly insulin resistance, generation of reactive oxygen species during alcohol metabolism, adipokines from visceral adipose tissue, and endotoxin derived from the gut. Although the pathogenesis of ALD has been widely investigated, the precise mechanisms are yet to be elucidated and many questions remain. This article reviews the possible mechanisms for the development of ALD identified to date.     

Optimal management for alcoholic liver disease: Conventional medications,natural therapy or combination?

Alcohol consumption is the principal factor in the pathogenesis of chronic liver diseases. Alcoholic liver disease (ALD) is defined by histological lesions on the liver that can range from simple hepatic steatosis to more advanced stages such as alcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma and liver failure. As one of the oldest forms of liver injury known to humans, ALD is still a leading cause of liver-related morbidity and mortality and the burden is exerting on medical systems with hospitalization and management costs rising constantly worldwide. Although the biological mechanisms, including increasing of acetaldehyde, oxidative stress with induction of cytochrome p450 2E1, inflammatory cytokine release, abnormal lipid metabolism and induction of hepatocyte apoptosis, by which chronic alcohol consumption triggers serious complex progression of ALD is well established, there is no universally accepted therapy to prevent or reverse. In this article, we have briefly reviewed the pathogenesis of ALD and the molecular targets for development of novel therapies. This review is focused on current therapeutic strategies for ALD, including lifestyle modification with nutrition supplements, available pharmacological drugs and new agents that are under development, liver transplantation, application of complementary medicines, and their combination. The relevant molecular mechanisms of each conventional medication and natural agent have been reviewed according to current available knowledge in the literature. We also summarized efficacy vs safety on conventional and herbal medicines which are specifically used for the prevention and treatment of ALD. Through a system review, this article highlighted that the combination of pharmaceutical drugs with naturally occurring agents may offer an optimal management for ALD and its complications. It is worthwhile to conduct large-scale, multiple centre clinical trials to further prove the safety and benefits for the integrative therapy on ALD.