Lymphocyte recruitment in alcoholic hepatitis

酒精性肝炎中的淋巴细胞募集

• 批准号: 7058862
• 负责人: DAVID H ADAMS
• 金额: $ 15.82万
• 依托单位: UNIVERSITY OF BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7058862
• 关键词: Kupffer' s cell; acetaldehyde; alcoholic hepatitis; amine oxidase (flavin); biological signal transduction; cell adhesion; cell adhesion molecules; cell migration; chemokine receptor; clinical research; ethanol; hemodynamics; human subject; liver cells; lymphocyte; nuclear factor kappa beta; patient oriented research; tissue /cell culture

DESCRIPTION (provided by applicant): Although alcoholic liver disease (ALD) is a major public health problem how alcohol stimulates inflammatory damage in the liver is poorly understood. Alcoholic hepatitis (AH), characterized by chronic inflammation and parenchymal infiltration by T cells and neutrophils via the sinusoids, is a critical determinant of disease progression. Circulating lymphocytes must recognize and bind to endothelial cells before they can enter tissue and there is evidence that specific combinations of chemokines and adhesion molecules regulate binding to sinusoidal endothelium including the novel adhesion molecule VAP-1 and CXCRS-binding chemokines, all of which show increased he expression in AH. VAP-1 is a monoamine oxidase and its enzymic activity appears to be critical for its adhesive function. We have developed an in vitro model in which human sinusoidal endothelial cells are grown under conditions of blood flow that mirror those in vivo allowing us to study lymphocyte interactions with endothelium at physiological flow rates. In addition we have adapted this assay for co-cultures of endothelial cells and hepatocytes or Kupffer cells allowing us to study the contribution of cell types on lymphocyte recruitment in response to alcohol. Specific aims are: 1) to determine if lymphocytes from patients with AH show increased adhesion to sinusoidal endothelium and if so to demonstrate the molecules involved, 2) to define the role of specific molecules including VAP-1 and CXCR3 in this process, 3) to use flow-based co-cultures to determine if alcohol and acetaldehyde activate sinusoidal endothelium and lymphocyte transmigration directly or via paracrine effects mediated by Kupffer cells or hepatocytes, 4) to define the role of NFkB signaling in ethanol mediated endothelial activation. These studies are unique because they investigate the adhesion of human cells under flow. They offer us the opportunity to determine the molecules involved in liver-infiltration in alcoholic hepatitis and how alcohol and its metabolites activate these processes. Understanding the molecular basis of lymphocyte adhesion to sinusoidal endothelium in ALD will elucidate the pathogenesis of liver damage and may suggest new therapeutic targets to prevent tissue-damage in response to alcohol.

描述（由申请人提供）：虽然酒精性肝病（ALD）是一个主要的公共卫生问题，但人们对酒精如何刺激肝脏炎症损伤知之甚少。酒精性肝炎 (AH) 的特征是慢性炎症以及 T 细胞和中性粒细胞通过血窦的实质浸润，是疾病进展的关键决定因素。循环淋巴细胞在进入组织之前必须识别并结合内皮细胞，有证据表明趋化因子和粘附分子的特定组合可调节与窦内皮的结合，包括新型粘附分子 VAP-1 和 CXCRS 结合趋化因子，所有这些都表现出增加他的表情是啊。 VAP-1 是一种单胺氧化酶，其酶活性似乎对其粘附功能至关重要。我们开发了一种体外模型，其中人窦内皮细胞在反映体内血流条件下生长，使我们能够研究淋巴细胞在生理流速下与内皮的相互作用。此外，我们已将该测定法应用于内皮细胞和肝细胞或库普弗细胞的共培养，使我们能够研究细胞类型对酒精反应中淋巴细胞募集的贡献。 具体目标是：1) 确定 AH 患者的淋巴细胞是否表现出对窦内皮的粘附增加，如果是，则证明所涉及的分子，2) 确定包括 VAP-1 和 CXCR3 在内的特定分子在此过程中的作用，3)使用基于流的共培养来确定酒精和乙醛是否直接或通过库普弗细胞或肝细胞介导的旁分泌作用激活窦内皮和淋巴细胞迁移， 4) 定义NFkB信号在乙醇介导的内皮激活中的作用。 这些研究是独特的，因为它们研究了流动下人体细胞的粘附。它们为我们提供了确定参与酒精性肝炎肝脏浸润的分子以及酒精及其代谢物如何激活这些过程的机会。了解 ALD 中淋巴细胞粘附到肝窦内皮的分子基础将阐明肝损伤的发病机制，并可能提出新的治疗靶点，以防止酒精引起的组织损伤。