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

 描述(由申请人提供)：酒精使用障碍影响着美国近2000万人，是全球可预防的发病率和死亡率的主要原因。持续、长期的酗酒是酒精性肝病(ALD)发生和发展的基础，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)、肝硬变，甚至进展为肝癌。ALD在人类中的发病机制仍然知之甚少，几十年来治疗方案一直没有改变。尽管如此，来自人类和动物研究的数据表明，先天性免疫系统在ALD中发挥着强大的作用。最近，一种新出现的小鼠酒精喂养模型已经建立起来，类似于人类早期的急性酒精中毒。酒精摄取的慢性/暴饮式(Gao-binger或NIAAA模型)模型将建立一些未知的AH特征的机制，即显著的肝细胞损伤和相关免疫细胞的渗透，如中性粒细胞。巨噬细胞迁移抑制因子(MIF)是一种具有趋化因子和细胞因子样活性的天然免疫调节因子，先前被认为是慢性酒精喂养小鼠ALD早期的关键因素。随着一种极端严重的酒精喂养模型的出现，我们试图确定MIF在小鼠慢性/狂饮酒精喂养后的作用。令我们惊讶的是，MIF缺陷小鼠肝细胞损伤的标志物增加，白细胞浸润，肝脏炎症基因表达增加，表明MIF是AH的肝脏保护因子。因此，我们假设，MIF通过抑制趋化因子的表达和随后的白细胞向肝实质的渗透来保护慢性/暴食喂养后的肝细胞损伤。为了探讨MIF在慢性/酗酒模型中的确切保护作用(S)，我们将利用MIF在小鼠中进行功能丧失和功能获得的研究，以确定慢性/酗酒后趋化因子、白细胞渗透和肝细胞损伤的关键变化。在动物身上产生的结果指导的机制研究将描绘特定的，MIF介导的分子靶点，对急性严重的乙醇诱导的肝损伤至关重要。拟议的研究可能为治疗人类ALD的新治疗策略提供理论基础。

 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.