Inhibition of Sterile Inflammation by Digoxin in Alcoholic Hepatitis

摘要：酒精性肝炎是一种重要的肝病，住院死亡率在25%-40%之间。 肝脏炎症是急性肝炎的一个关键特征，但驱动这种炎症反应的因素尚不清楚。 我们已经确定了肝脏炎症的新的关键驱动因素，这是这一应用的主题。我们还有 发现了新的蛋白组学和分子标记，将用于预测预后。 我们已经证明，核(缺氧抑制因子1-：HIF-1)通路的激活是必需的 提示抑制低氧诱导因子-1的作用可能是 治疗中的AH[1]。在高通量筛查中，心脏糖苷被鉴定为具有显著的能力 抑制HIF-1[2]。初步数据显示：1)HIF-1依赖基因在肝组织中表达上调 来自InTeam联合体的早期AH与重度AH相比，II)地高辛减少组织的能力 损伤模型中的酒精，以及其他形式的肝脏损伤。Iii)地高辛与丙酮酸激酶结合 M2(PKM2)，iv)地高辛减少PKM2与HIF-1启动子的结合并限制HIF-1的上调，以及 低氧诱导因子-1反应基因。V)基于适体的血清蛋白质组学分析表明，在AH患者中 和全身炎症反应(SIRS)肿瘤坏死因子相关蛋白增加， 低亲和力免疫球蛋白γFc区受体II、补体成分、激肽释放酶和成纤维细胞 增长因素。六)已知血清DNA是一种促炎配体，血清DNA水平与 急性肝炎患者外周血白细胞计数。 目的1.获得支持地高辛治疗酒精性肝炎的临床资料。 目的2.确定在酒精性肝炎中受PKM2调控的主要靶点和新靶点。 目的3.获取血浆蛋白质组和分子数据，以便对SIRS患者进行早期识别。 总而言之，这将使我们能够获得必要的数据，用于临床测试小剂量地高辛治疗急性肝炎。在……里面 此外，它将使我们能够在患者的血清中识别新的蛋白质标记物和促炎信号 和阿赫。最后，我们将能够确定是否有任何新的蛋白质标记与新的PKM2相关 我们已经确定了路径。

ABSTRACT: Alcoholic hepatitis (AH) is a major liver disease, and has an inpatient mortality of between 25-40%. Liver inflammation is a key feature of AH, yet the factors which drive this inflammatory response are not known. We have identified novel key drivers of liver inflammation which are the subject of this application. We have also identified novel proteomic and molecular markers in AH which will be used to predict prognosis. We have shown that activation of the nuclear (hypoxia inhibitory factor 1-: HIF-1) pathway was required for the development of sustained sterile inflammation, which suggested that inhibition of HIF-1 may be therapeutic in AH[1]. In a high throughput screen cardiac glycoside were identified to have significant ability to inhibit HIF-1[2]. The preliminary data demonstrates i) Up-regulation of HIF-1 dependent genes in liver tissues from early AH, as compared to severe AH, from the InTeam consortium ii) Ability of digoxin to reduce tissue damage in a model of alcohol, and others forms of liver injury. iii) Digoxin binds to the enzyme pyruvate kinase M2 (PKM2), iv) Digoxin reduces PKM2 binding to the HIF-1 promoter and limits up-regulation of HIF-1, and HIF-1 response genes. v) An aptamer based proteomic analysis of serum shows that in patients with the AH and the systemic inflammatory response (SIRS) there is an increase in tumor necrosis factor related proteins, low affinity immunoglobulin gamma Fc region receptor II, complement components, kallikrein and fibroblast growth factors. vi) Serum DNA is known to be a pro-inflammatory ligand and serum DNA levels correlated with peripheral blood white cell count in AH. Aim 1. Obtain clinical data supporting the therapeutic use of digoxin in alcoholic hepatitis. Aim 2. Identify dominant and novel targets that are regulated by PKM2 in alcoholic hepatitis. Aim 3. Obtain plasma proteomic and molecular data to allow for early identification of patients with SIRS. Collectively this will allow us to obtain the necessary data towards clinically testing low dose digoxin in AH. In addition, it will allow us to identify novel protein markers and pro-inflammatory signals in the serum of patients with AH. Finally, we will be able to identify if any of the novel protein markers are associated with the novel PKM2 pathway we have identified.