Complement inhibition as sepsis therapy

补体抑制作为败血症治疗

• 批准号: 8024071
• 负责人: JOHN D LAMBRIS
• 金额: $ 53.52万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 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/8024071
• 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

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. ) PUBLIC HEALTH RELEVANCE: Sepsis is a multi-factorial disorder whose underlying pathophysiologic mechanisms are not yet known; therefore the quest for effective life-saving therapies remains elusive. In an attempt to bridge the gap between basic research on small animals and clinical research, this application addresses the use of a model with relevance to human disease to investigate whether inhibition of complement activation alone or as a combination therapy could prevent organ dysfunction and improve clinical outcome of sepsis. Owing to the resemblance with the human disease, the proposed studies have the potential to facilitate the translation of the mechanisms and therapies into the clinic and lead to a true bench-to-bed approach. )

描述（由申请人提供）：严重败血症导致全身炎症，其中凝血和补体激活起关键作用。来自患者和动物模型的证据表明，脓毒症是一种多阶段、多因素的疾病，其中对入侵细菌的早期暴发性炎症反应导致低灌注和缺血再灌注（IR）损伤，进而发展为多器官衰竭（MOF）并最终导致死亡。我们实验室的工作表明，使用亚致死剂量的大肠杆菌在动物中诱发的严重败血症分为两个阶段，每个阶段由不同的病理生理驱动。第一阶段的事件是由病原体的直接影响引起的，而第二阶段是由于IR后宿主的异常恢复而发生的。本研究的目的是研究单独抑制补体激活或联合抑制补体激活是否可以预防MOF并改善败血症的预后。目的1将使用C3转化酶抑制剂来确定补体在败血症的两个阶段中的作用，评估补体激活作为败血症中血小板减少的潜在原因，并确定补体抑制在败血症进展中的器官特异性保护作用。本研究将采用cDNA微阵列、免疫细胞化学、电子显微镜和重要器官生化分析来鉴定补体激活产物对控制脓毒症进展的主要病理生理过程的影响。在我们的脓毒症模型中，目的2将确定重组凝血调节蛋白（TM-LLD）凝集素样结构域的补体抑制是否以及通过何种机制可以预防器官衰竭并改善预后。目的3将确定与单独的补体抑制相比，补体阻断与CD14或细胞外组蛋白的免疫抑制是否能提供更好/额外的治疗效果。该项目有可能促进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用于败血症诱导的器官衰竭的有效治疗。