IL-6 and hepatic dysfunction in sepsis

IL-6 与脓毒症肝功能障碍

• 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
• 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

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、危及生命的疾病，其发病率正在上升。在美国，它造成了20多万人死亡，医疗保健支出超过167亿美元。这种致命疾病的治疗是支持性的，因为人们对其潜在的病理生理学知之甚少。败血症的正常自然病史已经有了很好的定义。它呈现出一种高代谢、高炎症状态。幸运的是，临床医生已经相当熟练地处理了这一阶段的综合征，因此早期死亡的情况很少。随着时间的推移，患者的病情会演变成器官功能减退的状态，即多器官功能障碍综合症(MODS)。大多数败血症相关死亡发生在MODS患者中，通常反映免疫系统功能下降。免疫功能障碍的发生可能是因为免疫细胞停止功能或改变其功能模式。如果免疫功能障碍代表了MODS的一个组成部分，那么假设其他器官也会发生类似的变化--功能降低或改变--是合乎逻辑的。在我们的研究中，我们研究了这种可能性在肝细胞，或肝细胞。使用脓毒症的小鼠模型，我们已经表明，肝细胞功能随着时间的推移而发生戏剧性的变化，在面对严重的，而不是轻度的脓毒症时。这种变化的性质尚不清楚，因此缺乏治疗方法。我们认为，这种变化是由于肝细胞对单个细胞外的信号做出反应的途径发生了变化。这些信号可能由其他肝细胞、血流中的细胞或溶解在血液中的分子启动。潜在的缺陷可能是细胞未能为生化反应产生能量。我们将检查对单一介质EL-6的反应，并确定IL-6信号通路在脓毒症中是否受损。我们还将研究脓毒症对一种关键酶的影响，该酶负责在肝细胞中产生能量。最后，我们将确定El-6管理是否可以扭转这一缺陷。这些研究应该提供有关败血症生物学的重要信息，并建议新的治疗方法。