IL-6 AND HEPATIC DYSFUNCTION IN SEPSIS

IL-6 与脓毒症中的肝功能障碍

• 批准号: 6131852
• 负责人: CLIFFORD Scott DEUTSCHMAN
• 金额: $ 25.36万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6131852
• 关键词: blood toxicology; cholanate compound; cholestasis; gel mobility shift assay; gene expression; genetic transcription; interleukin 6; laboratory mouse; liver cells; liver disorder; liver function; membrane transport proteins; multiple organ failure; nuclear runoff assay; nucleoproteins; protein structure function; transcription factor; transfection /expression vector; western blottings

DESCRIPTION ( Applicant's abstract.) Sepsis and the related Systemic Inflammatory Response Syndrome (SIRS) and Multiple Organ Dysfunction Syndrome (MODS) are important causes of death and disability in surgical or injured patients, although the exact cause of death is often obscure. These disorders are complex, involve a number of molecular mediators and effect most organs. Little is understood, however, about the manner in which organ dysfunction develops in these diseases. One important organ that is damaged in sepsis/SIRS/MODS is the lever. Intra-abdominal fecal contamination causes SIRS/MODS-like abnormalities in the liver of rodents. In this study we will examine one proposed mechanism that we believe contributes to the development of liver dysfunction in sepsis /SIRS/MODS. We have shown that intra-abdominal fecal contamination causes an early down regulation of transcription in this organ. This change affects many genes, including some encoding molecules that 1) transfer bile acids out of liver cells and into the biliary system and 2) allow liver cells to burn fat. We propose that the inflammatory cytokine IL-6 mediates some aspects of decreased gene expression, leading to liver cells that cannot excrete bile salts or burn fat. A build-up of bile salts and fat in liver cells "poisons" them so that they die. When enough liver cells die, liver dysfunction develops. The role played by IL-6 in this proposed mechanism of hepatic dysfunction will be studied in the setting of normal IL-6 levels, IL-6 absence, IL-6 excess and IL-6 repletion after depletion. Several specific measures will be studied. These include 1) transcription of the bile acid transporters Ntcp and Mrp2 and the rate-limiting enzyme in fat oxidation, CPTII, to be determined using transcription elongation analysis, 2) activation of two hepatic nuclear proteins, C/EBPalpha and HNF-1alpha, that modulate transcription of Ntcp, Mrp2 and CPTII and 3) the development of cholestasis (bile trapping in cells) and steatosis (fat trapping in cells) as indicated by microscopic examination of fixed liver sections. In addition, we will mimic IL-6 levels in sepsis in normal mice by 1) administering intravenous IL-6 and 2) injecting a virus that is taken up by the liver and produces high intrahepatic levels of IL-6. We will then study transcription, transcription factor activation, cholestasis and steatosis. These studies should provide key information on the role played by an important inflammatory mediator, IL-6, in the complex series of events that results in the hepatic dysfunction of SIRS/MODS.

描述（申请人的摘要。）败血症和相关的系统性 炎症反应综合征（SIR）和多器官功能障碍 综合征（mod）是手术中的死亡和残疾的重要原因 受伤的患者，尽管确切的死亡原因常常晦涩难懂。这些 疾病很复杂，涉及许多分子介质，并且最大 器官。然而，几乎没有什么理解的关于器官的方式 功能障碍在这些疾病中发展。一个受损的重要器官 败血症/sir/mod是杠杆。腹腔内粪便污染原因 啮齿动物肝脏中的Sir/mod样异常。在这项研究中，我们将 检查一种提出的机制，我们认为有助于发展 败血症 /sir /mods中的肝功能障碍。我们已经表明腹腔内 粪便污染会引起早期的转录调节 器官。这种变化影响了许多基因，包括一些编码分子 1）将胆汁酸从肝细胞中转移到胆道系统中，2） 允许肝细胞燃烧脂肪。我们建议炎性细胞​​因子IL-6 介导降低基因表达的某些方面，导致肝细胞 不能排泄胆汁盐或燃烧脂肪。胆汁盐和脂肪的积聚 肝细胞“毒药”它们，以使它们死亡。当足够的肝细胞死亡时，肝脏 功能障碍发展。 IL-6在这种提议的机制中所扮演的角色 将在正常IL-6水平的情况下研究肝功能障碍，IL-6 缺失，耗尽后的IL-6过量和IL-6补充。几个具体 将研究措施。其中包括1）胆汁酸的转录 转运蛋白NTCP和MRP2以及脂肪氧化中的速率限制酶， CPTII，使用转录伸长分析确定，2）激活 在调节的两个肝核蛋白C/EBPALPHA和HNF-1Alpha中 NTCP，MRP2和CPTII的转录以及3）胆汁淤积的发展 （胆汁捕获在细胞中）和脂肪变性（细胞中的脂肪诱捕），如 固定肝切片的显微镜检查。此外，我们将模仿 正常小鼠败血症的IL-6水平通过1）给予静脉注射IL-6和 2）注入由肝脏吸收并产生高的病毒 IL-6的肝内水平。然后，我们将研究转录，转录 因子激活，胆汁淤积和脂肪变性。这些研究应提供关键 有关重要炎症介质IL-6的作用的信息 一系列复杂的事件导致肝功能障碍 SIRS/MODS。