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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：
7596297
负责人：
CLIFFORD Scott DEUTSCHMAN
金额：
$ 30.65万
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 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7596297
关键词：
Accounting Address Animals Attenuated Biochemical Reaction Biology Blood Cells Cessation of life Cholestasis Communication Complex Cytokine Inducible SH2-Containing Protein DNA Binding Defect Development Disease Dose Enzymes Equilibrium Face Failure Functional disorder Gene Expression Glucagon Glucose Harvest Health Expenditures Hepatic Hepatocyte Histologic Histology Hormonal Hour Human Hypoxia Immune Immune System Diseases Immune system Incidence Indium 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 Mitochondria Modeling Morbidity - disease rate Multiple Organ Failure Mus Myocardium Natural History Nature Necrosis Normal Cell Organ Outcome Oxidative Phosphorylation PTPN11 gene Pathogenesis Pathway interactions Patients Pattern Perfusion 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 depression design extracellular genetic regulatory protein improved inhibitor/antagonist member mortality mouse model novel therapeutic intervention programs protein expression research study response sensor septic transcription factor

项目摘要

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 $16.7billion in health care expenditures. Treatment of this lethal disorder is supportive because the underlying pathophysiology is poorly understood. The normal natural history of epsis 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, weexamine 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 anindividual 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-6signaling 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-6administration can reverse the defect. These studies should provide important information regarding septic biology and suggest novel therapeutic approaches.

脓毒症是一种重要的、危及生命的疾病，其发病率正在上升。在美国，它占到了超过20万人死亡，医疗保健支出超过167亿美元。对这种致命疾病的治疗是支持的，因为人们对潜在的病理生理学知之甚少。人类正常的自然历史 Epsis已经被很好地定义了。它呈现出一种高代谢、高炎症状态。幸运的是，临床医生已经非常熟练地处理这一阶段的综合征，因此早期死亡是罕见的。完毕随着时间的推移，患者的病情发展到器官功能减退、多器官功能障碍的状态综合征(MODS)。大多数败血症相关死亡发生在MODS患者中，通常表现为减少。免疫系统功能。由于免疫细胞停止功能或改变，可能会发生免疫功能障碍他们的功能模式。如果免疫功能障碍代表了MODS的一个组成部分，那么我们就有理由认为类似的变化--功能降低或改变--发生在其他器官中。在我们的研究中，我们检查这种可能性存在于肝细胞或肝细胞中。使用脓毒症的小鼠模型，我们已经证明了肝细胞随着时间的推移，在面对严重的、而不是轻微的脓毒症时，功能会发生戏剧性的变化。的性质这种变化是未知的，因此缺乏治疗方法。我们认为，更改的结果由于肝细胞对来自个体外的信号做出反应的路径的改变手机。这些信号可能是由其他肝细胞、血流中的细胞或溶解在鲜血。潜在的缺陷可能是细胞未能产生生化所需的能量。反应。我们将检查对单个介质EL-6的反应，并确定IL-6信号是否脓毒症时通路受损。我们还将研究脓毒症对一种关键酶的影响，即负责在肝细胞中产生能量。最后，我们将确定El-6政府是否可以逆转这个缺陷。这些研究应该提供有关败血症生物学的重要信息，并提出新的治疗方法。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mitochondrial dysfunction and resuscitation in sepsis.

DOI：
10.1016/j.ccc.2010.04.007
发表时间：
2010-07
期刊：
Critical care clinics
影响因子：
4.3
作者：
Ruggieri AJ;Levy RJ;Deutschman CS
通讯作者：
Deutschman CS

Adenoviral vector transfection into the pulmonary epithelium after cecal ligation and puncture in rats.

大鼠盲肠结扎和穿刺后腺病毒载体转染至肺上皮。

DOI：
10.1097/00000542-200110000-00029
发表时间：
2001
期刊：
Anesthesiology
影响因子：
8.8
作者：
Weiss,YG;Tazelaar,J;Gehan,BA;Bouwman,A;Christofidou-Solomidou,M;Yu,QC;Raj,N;Deutschman,CS
通讯作者：
Deutschman,CS

Adenoviral transfer of HSP-70 into pulmonary epithelium ameliorates experimental acute respiratory distress syndrome.