IL-6 and hepatic dysfunction in sepsis

IL-6 与脓毒症肝功能障碍

基本信息

批准号：
7210728
负责人：
CLIFFORD Scott DEUTSCHMAN
金额：
$ 30.64万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-06-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7210728
关键词：
Accounting Address Animals Attenuated Biochemical Reaction Biology Blood Cells Cessation of life Cholestasis Communication Complex Condition Cytokine Inducible SH2-Containing Protein DNA Binding Defect Development Disease Dose Enzymes Equilibrium Face Failure Functional disorder Gene Activation Gene Expression Glucagon Glucose Harvest Health Expenditures Hepatic Hepatocyte Histologic Histology Hormonal Hour Human Hypoxia Immune Immune System Diseases Immune system Incidence Indium Individual Inflammation Injection of therapeutic agent Insulin Interleukin-6 Interleukins Investigation JAK1 gene Janus kinase Life Ligation Link Liver Liver Dysfunction Liver Mitochondria Macroglobulins Mediating Mediator of activation protein Mental Depression Mitochondria Modeling Morbidity - disease rate Multiple Organ Failure Mus Myocardium Natural History Nature Necrosis Normal Cell Numbers Organ Outcome Oxidative Phosphorylation PTPN11 gene Pathogenesis Pathway interactions Patients Pattern Perfusion Personal Satisfaction Phase Phenylephrine Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Portal vein structure Preparation Process Protein Dephosphorylation Protein Family Protein Tyrosine Kinase Proteins Puncture procedure Recombinants Research Personnel Role Sepsis Series Signal Pathway Signal Transduction Stat3 protein Stream Syndrome Testing Therapeutic Time Tissues Transduction Gene Tyrosine Phosphorylation United States Wild Type Mouse Work cohort computerized data processing cytochrome c cytochrome c oxidase cytokine design extracellular genetic regulatory protein improved inhibitor/antagonist member mortality mouse model novel therapeutics programs protein expression research study response sensor septic transcription factor

项目摘要

DESCRIPTION (provided by applicant): Sepsis is an important, life-threatening disease whose incidence is rising. In the United States, it accounts for more than 200,000 deaths and over $16.7 billion in health care expenditures. Treatment of this lethal disorder is supportive because the underlying pathophysiology is poorly understood. The normal natural history of sepsis has been well-defined. It presents with a hypermetabolic, hyperinflammatory state. Fortunately, clinicians have become quite adept at managing this phase of the syndrome so death early on is rare. Over time, the patient's condition evolves to a state of reduced organ function, the Multiple Organ Dysfunction Syndrome (MODS). Most sepsis-associated deaths occur in patients with MODS and often reflect decreased immune system function. Immune dysfunction may occur because immune cells cease to function or change their pattern of function. If immune dysfunction represents one component of MODS, it is logical to assume that similar changes - either decreased or altered function - occur in other organs. In our studies, we examine this possibility in liver cells, or hepatocytes. Using a mouse model of sepsis, we have shown that hepatocyte function changes dramatically over time and in the face of severe, as opposed to mild, sepsis. The nature of this change is unknown and therefore therapeutic approaches are lacking. We propose that the change results from an alteration in the pathways by which hepatocytes respond to signals that arise outside an individual cell. These signals may be initiated by others liver cells, cells in the blood stream or molecules dissolved in the blood. The underlying defect may result from a failure of cells to generate energy for biochemical reactions. We will examine the response to a single mediator, EL-6, and determined if the IL-6 signaling pathway is impaired in sepsis. We also will investigate the effects of sepsis on a key enzyme that is responsible for generating energy in liver cells. Finally, we will determine if EL-6 administration can reverse the defect. These studies should provide important information regarding septic biology and suggest novel therapeutic approaches.

描述（由申请人提供）：败血症是一种重要的，威胁生命的疾病，其发病率正在上升。在美国，它占死亡人数超过200,000多人，卫生保健支出超过167亿美元。这种致命疾病的治疗是支持的，因为理解的潜在病理生理学知之甚少。脓毒症的正常自然病史已明确定义。它具有多代谢，高炎性状态。幸运的是，临床医生已经非常擅长管理综合征的这一阶段，因此很少见。随着时间的流逝，患者的病情演变成降低器官功能的状态，即多器官功能障碍综合征（MODS）。大多数与败血症相关的死亡发生在MOD患者中，通常反映了免疫系统功能降低。免疫功能障碍可能会发生，因为免疫细胞无法发挥作用或改变其功能模式。如果免疫功能障碍代表MOD的一个组成部分，则合乎逻辑地假设其他器官中发生类似的变化（降低或变化）。在我们的研究中，我们在肝细胞或肝细胞中检查了这种可能性。使用败血症的小鼠模型，我们表明肝细胞功能随着时间的流逝而与轻度败血症相反，肝细胞功能随着时间的变化而发生巨大变化。这种变化的性质是未知的，因此缺乏治疗方法。我们建议变化是由于肝细胞对单个细胞外出现的信号响应的途径的改变而导致的。这些信号可以由其他肝细胞，血流中的细胞或溶解在血液中的分子引发。潜在的缺陷可能是由于细胞未能产生生化反应的能量而导致的。我们将检查对单个介体EL-6的反应，并确定败血症中IL-6信号通路是否受损。我们还将研究败血症对负责在肝细胞中产生能量的关键酶的影响。最后，我们将确定EL-6给药是否可以逆转缺陷。这些研究应提供有关化粪池生物学的重要信息，并提出新型的治疗方法。