Role of macrophage migration inhibitory factor in an acutely severe model of alcoholic hepatitis

巨噬细胞迁移抑制因子在急性重型酒精性肝炎模型中的作用

• 批准号: 9122113
• 负责人: Kyle Poulsen
• 金额: $ 5.61万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-16 至 2019-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122113
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic liver damage; Alleles; Animal Disease Models; Animal Model; Animals; Biological Response Modifiers; CD44 gene; CXC Chemokines; CXCR; Cell Communication; Cells; Cessation of life; Chemotactic Factors; Chronic; Cirrhosis; Communications Media; Complement; Complex; Development; Disease; Distant; Environment; Ethanol; Family; Flow Cytometry; Gene Expression; Golgi Apparatus; Hepatocellular Damage; Human; Immigration; Immune; Immune system; Immunohistochemistry; Individual; Infiltration; Inflammatory; Inflammatory Response; Injury; Internet; Leukocyte Chemotaxis; Leukocytes; Liver; Liver parenchyma; Malignant neoplasm of liver; Mediating; Messenger RNA; Migration Inhibitory Factor; Modeling; Molecular Target; Morbidity - disease rate; Mus; National Institute on Alcohol Abuse and Alcoholism; Natural Immunity; Neutrophilic Infiltrate; Organ; Pathogenesis; Patients; Plasma; Play; Property; Proteins; Protocols documentation; Recruitment Activity; Regulation; Reporting; Rheumatoid Arthritis; Role; Sepsis; Signal Transduction; Staging; Stimulus; Systemic Lupus Erythematosus; Testing; Therapeutic; Therapeutic Intervention; Tissues; United States; Work; alcohol exposure; alcohol use disorder; base; binge drinking; chemokine; cytokine; design; drinking behavior; exosome; extracellular vesicles; feeding; gain of function; human data; intercellular communication; liver injury; loss of function; macrophage; monocyte; mortality; mouse model; neutralizing antibody; neutrophil; novel therapeutics; phenylpyruvate tautomerase; prevent; public health relevance; receptor; response; response to injury; small molecule inhibitor

 DESCRIPTION (provided by applicant): Alcohol Use Disorder affects nearly 20 million individuals in the United States and is a major cause of preventable morbidity and mortality worldwide. Continuous, chronic alcohol abuse underlies the initiation and progression Alcoholic Liver Disease (ALD), attributable to 18,000 deaths in 2013 in the USA. ALD is a spectrum disorder encompassing steatosis, alcoholic hepatitis (AH), cirrhosis and even progressing to liver cancer. The pathogenesis of ALD in humans remains poorly understood and therapeutic options remain unchanged for decades. Despite this, data from human and animal studies demonstrate a robust role for the innate immune system in ALD. Recently, an emerging model of ethanol feeding in mice that resembles early AH in humans has been established. The Chronic/Binge (Gao-Binge or NIAAA model) model of ethanol feeding will establish mechanisms underlying several unknown features of AH, namely marked hepatocellular damage and infiltration of relevant immune cells, such as neutrophils. Macrophage Migration Inhibitory Factor (MIF), a regulator of innate immunity with chemokine- and cytokine-like activities, was previously identified as a key contributor to the early stage of ALD after chronic ethanol feeding to mice. With the advent of an acutely severe model of ethanol feeding, we sought to determine the role of MIF following Chronic/Binge ethanol feeding in mice. Much to our surprise, MIF-deficient mice had increased markers of hepatocellular damage, leukocyte infiltration, and increased inflammatory gene expression in the liver, suggesting that MIF is a hepatoprotective factor in AH. We therefore hypothesized that MIF protects from hepatocellular damage following Chronic/Binge feeding via MIF-mediated suppression of chemokine expression and subsequent leukocyte infiltration into the hepatic parenchyma. To interrogate the precise protective role(s) that MIF is playing in the Chronic/Binge model of ethanol feeding, we will perform loss-of-function and gain-of-function studies with MIF in mice to identify key changes in chemotactic factors, leukocyte infiltration and hepatocellular damage following Chronic/Binge ethanol feeding. Mechanistic studies guided by the results generated in animals will delineate specific, MIF-mediated molecular targets critical to acutely severe ethanol- induced liver injury. The proposed studies could provide rationale for novel therapeutic strategies to treat ALD in humans.

 酒精使用障碍影响美国近2000万人，是全球可预防的发病率和死亡率的主要原因。持续的慢性酒精滥用是酒精性肝病（ALD）开始和进展的基础，2013年美国有18，000人死亡。ALD是一种谱系疾病，包括脂肪变性、酒精性肝炎（AH）、肝硬化甚至进展为肝癌。ALD在人类中的发病机制仍然知之甚少，几十年来治疗选择保持不变。尽管如此，来自人类和动物研究的数据证明了先天免疫系统在ALD中的强大作用。最近，已经建立了一种类似于人类早期AH的小鼠乙醇喂养模型。乙醇喂养的慢性/狂欢（Gao-Binge或NIAAA模型）模型将建立AH的几个未知特征的机制，即显著的肝细胞损伤和相关免疫细胞（如中性粒细胞）的浸润。巨噬细胞迁移抑制因子（MIF），一种具有趋化因子和类胡萝卜素活性的先天免疫调节因子，先前被确定为慢性乙醇喂养小鼠后ALD早期阶段的关键贡献者。随着急性严重乙醇喂养模型的出现，我们试图确定慢性/酗酒乙醇喂养小鼠后MIF的作用。令我们惊讶的是，MIF缺陷小鼠肝细胞损伤，白细胞浸润和增加的炎症基因表达的标志物增加，这表明MIF是AH的肝保护因子。因此，我们假设MIF通过MIF介导的趋化因子表达抑制和随后的白细胞浸润到肝实质中来保护慢性/暴食后的肝细胞损伤。为了探究MIF在慢性/酗酒乙醇喂养模型中发挥的确切保护作用，我们将在小鼠中使用MIF进行功能丧失和功能获得研究，以确定慢性/酗酒乙醇喂养后趋化因子、白细胞浸润和肝细胞损伤的关键变化。由动物中产生的结果指导的机制研究将描绘对急性重度乙醇诱导的肝损伤至关重要的特异性MIF介导的分子靶点。拟议的研究可以为治疗人类ALD的新治疗策略提供理论基础。