Complement inhibition as sepsis therapy

补体抑制作为败血症治疗

基本信息

批准号：
8466739
负责人：
JOHN D LAMBRIS
金额：
$ 50.28万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-02 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8466739
关键词：
Address Adverse effects Animal Model Animals Antibiotic Therapy Antibiotics Antibodies Attenuated Bacteremia Bacteria Basic Science Beds Biochemical Biological Preservation Blood Pressure CD14 gene Cessation of life Clinic Clinical Clinical Research Coagulation Process Combined Modality Therapy Complement Complement 3 Convertase Complement Activation Complement Inactivators Defense Mechanisms Disease Disease Progression Disease model Dose Electron Microscopy Equilibrium Escherichia coli Event Family suidae Functional disorder Genomics Goals Histones Human Imaging Techniques Immune response In Vitro Inflammation Inflammatory Inflammatory Response Infusion procedures Invaded Ischemia Kidney Lead Lectin Life Liver Lung Modeling Morbidity - disease rate Multiple Organ Failure Organ Organ failure Outcome Papio Pathogenesis Pathology Pathway interactions Patients Perfusion Play Process Recombinants Recovery Regimen Reperfusion Injury Reperfusion Therapy Research Rodent Role Sepsis Septic Shock Series Staging System Testing Therapeutic Effect Thrombocytopenia Thrombomodulin Time Tissues Toxic effect Translations Whole Blood Work activation product base cDNA Arrays complement system compstatin effective therapy extracellular human disease immunocytochemistry improved inhibitor/antagonist microbial mortality novel therapeutics pathogen prevent protective effect response

Address Adverse effects Animal Model Animals Antibiotic Therapy Antibiotics Antibodies Attenuated Bacteremia Bacteria Basic Science Beds Biochemical Biological Preservation Blood Pressure CD14 gene Cessation of life Clinic Clinical Clinical Research Coagulation Process Combined Modality Therapy Complement Complement 3 Convertase Complement Activation Complement Inactivators Defense Mechanisms Disease Disease Progression Disease model Dose Electron Microscopy Equilibrium Escherichia coli Event Family suidae Functional disorder Genomics Goals Histones Human Imaging Techniques Immune response In Vitro Inflammation Inflammatory Inflammatory Response Infusion procedures Invaded Ischemia Kidney Lead Lectin Life Liver Lung Modeling Morbidity - disease rate Multiple Organ Failure Organ Organ failure Outcome Papio Pathogenesis Pathology Pathway interactions Patients Perfusion Play Process Recombinants Recovery Regimen Reperfusion Injury Reperfusion Therapy Research Rodent Role Sepsis Septic Shock Series Staging System Testing Therapeutic Effect Thrombocytopenia Thrombomodulin Time Tissues Toxic effect Translations Whole Blood Work activation product base cDNA Arrays complement system compstatin effective therapy extracellular human disease immunocytochemistry improved inhibitor/antagonist microbial mortality novel therapeutics pathogen prevent protective effect response

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项目摘要

DESCRIPTION (provided by applicant): Severe sepsis leads to systemic inflammation, wherein coagulation and complement activation play critical roles. Evidence from patients and animal models suggest that sepsis is a multi-stage, multi-factorial disease in which the early fulminate inflammatory response to the invading bacteria leads to hypo-perfusion and ischemia-reperfusion (IR) injury that evolves to multiple organ failure (MOF) and ultimately to death. Work from our lab has demonstrated that severe sepsis induced in animals by using sublethal doses of E. coli develops as two-stage series of events, each stage being driven by different pathophysiologies. First stage events are caused by the direct effects of the pathogen, whereas the second stage occurs as result of an aberrant host recovery after IR. The objectives of this proposal are to investigate whether inhibition of complement activation alone or as combination therapies could prevent MOF and improve the outcome of sepsis. Aim 1 will use a C3 convertase inhibitor to determine the role of complement during each of the two stages of sepsis, assess complement activation as a potential cause of thrombocytopenia in sepsis and identify organ- specific protective effects of complement inhibition during sepsis progression. This research will employ cDNA microarray, immunocytochemistry, electron microscopy and biochemical analysis of vital organs to identify the effect of complement activation products on the dominant pathophysiologic processes controlling the progression of sepsis. Aim 2 will determine if, and through what mechanisms, complement inhibition by the recombinant lectin-like domain of thrombomodulin (TM-LLD) could prevent organ failure and improve outcome in our sepsis model. Aim 3 will determine whether combining complement blockade with immunological inhibition of CD14 or extracellular histones could provide superior/additional effects therapeutic effects on E. coli sepsis as compared to complement inhibition alone. This project has potential to advance our understanding of the role of complement activation in sepsis progression and to test whether complement inhibition could be used as effective therapy for sepsis-induced organ failure. )

描述（由申请人提供）：严重的败血症会导致系统性炎症，其中凝血和补体激活起着关键作用。来自患者和动物模型的证据表明，败血症是一种多阶段的多因素疾病，其中早期对入侵细菌的炎症反应导致炎症性低下和缺血 - 再灌注（IR）损伤（IR）损伤，它演变为多器官衰竭（MOF），并最终死亡。我们实验室的工作表明，通过使用大肠杆菌剂量的大肠杆菌作为两阶段的事件而导致动物引起的严重败血症，每个阶段都由不同的病理生理驱动。第一阶段事件是由病原体的直接影响引起的，而第二阶段是由于IR后异常宿主恢复而发生的。该提案的目标是研究抑制补体激活是单独的还是组合疗法可以防止MOF并改善败血症的结果。 AIM 1将使用C3转化酶抑制剂来确定败血症两个阶段中每个阶段的补体作用，评估补体激活是脓毒症中血小板减少症的潜在原因，并确定脓毒症进展过程中补体抑制的特定器官保护作用。这项研究将采用cDNA微阵列，免疫细胞化学，电子显微镜和重要器官的生化分析，以确定补体激活产物对控制败血症进展的主要病理生理过程的影响。 AIM 2将确定通过哪些机制补充血栓抑制蛋白（TM-LLD）的重组凝集素样结构域的补体抑制作用，可以防止器官衰竭并改善我们的败血症模型。 AIM 3将确定补体阻滞与CD14或细胞外组蛋白的免疫学抑制相比，与仅补体抑制相比，是否可以对大肠杆菌败血症产生出色/附加的治疗作用。该项目有可能提高我们对补体激活在败血症进展中的作用的理解，并测试补体抑制是否可以用作败血症诱导器官衰竭的有效治疗。）