IL-6 AND HEPATIC DYSFUNCTION IN SEPSIS

IL-6 与脓毒症中的肝功能障碍

• 批准号: 6520088
• 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/6520088
• 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（申请人摘要）脓毒症及相关全身性疾病 炎症反应综合征（SIRS）与多器官功能障碍 多器官功能不全综合征（MODS）是外科手术患者死亡和致残的重要原因， 受伤的病人，虽然死亡的确切原因往往是模糊的。这些 疾病是复杂的，涉及许多分子介质， 机关然而，人们对器官如何被移植的方式知之甚少。 在这些疾病中发展功能障碍。一个重要的器官受损， 脓毒症/SIRS/MODS是杠杆。腹腔内粪便污染原因 啮齿类动物肝脏中的SIRS/MODS样异常。在这项研究中，我们将 研究一个我们认为有助于发展的拟议机制， 脓毒症/SIRS/MODS中的肝功能障碍。我们已经证明，腹腔内 粪便污染导致转录的早期下调， 器官.这种变化会影响许多基因，包括一些编码分子， 1)将胆汁酸从肝细胞转移到胆道系统中，以及2） 让肝细胞燃烧脂肪我们认为炎症细胞因子IL-6 介导基因表达降低的某些方面，导致肝细胞， 不能排泄胆盐或燃烧脂肪。胆盐和脂肪的积累 肝细胞“毒害”它们，使它们死亡。当足够多的肝细胞死亡时， 功能障碍发展。IL-6在这一拟议的机制中发挥的作用， 将在IL-6水平正常的情况下研究肝功能障碍， 缺乏、IL-6过量和消耗后IL-6补充。几个具体 将研究措施。这些包括1）胆汁酸的转录 转运蛋白Ntcp和Mrp 2以及脂肪氧化中的限速酶， CPTII，使用转录延伸分析确定，2）激活 两种肝核蛋白C/EBPalpha和HNF-1 α， Ntcp、Mrp 2和CPTII的转录和3）胆汁淤积的发展 (bile捕获在细胞中）和脂肪变性（脂肪捕获在细胞中），如 固定肝脏切片的显微镜检查。此外，我们将模仿 正常小鼠中脓毒症中的IL-6水平，通过1）静脉内施用IL-6和 2)注射一种被肝脏吸收的病毒， 肝内IL-6水平。然后我们将学习转录，转录 因子激活、胆汁淤积和脂肪变性。这些研究将提供关键 关于重要的炎症介质IL-6在 导致肝功能不全的一系列复杂事件 SIRS/MODS。