Complement inhibition as sepsis therapy

描述（由申请方提供）：严重脓毒症导致全身性炎症，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，其演变为多器官衰竭（MOF）并最终导致死亡。本实验室的工作已经证明，用亚致死剂量的E.大肠杆菌作为两阶段系列事件发展，每个阶段由不同的病理生理学驱动。第一阶段的事件是由病原体的直接影响，而第二阶段发生的结果异常主机恢复后IR。本建议的目的是调查是否抑制补体激活单独或联合治疗可以防止MOF和改善脓毒症的结果。 目的1将使用C3转化酶抑制剂来确定补体在脓毒症的两个阶段中的每一个阶段中的作用，评估补体活化作为脓毒症中血小板减少症的潜在原因，并鉴定脓毒症进展期间补体抑制的器官特异性保护作用。本研究将采用基因芯片，免疫细胞化学，电子显微镜和生化分析的重要器官，以确定补体激活产物的影响，占主导地位的病理生理过程控制脓毒症的进展。目的2将确定重组凝血调节蛋白凝集素样结构域（TM-LLD）的补体抑制作用是否以及通过何种机制可以预防脓毒症模型中的器官衰竭并改善结局。目的3将确定是否结合补体阻断与免疫抑制CD 14或细胞外组蛋白可以提供上级/额外的效果治疗E。大肠杆菌脓毒症与单独的补体抑制相比。该项目有可能促进我们对补体激活在脓毒症进展中的作用的理解，并测试补体抑制是否可用作脓毒症诱导的器官衰竭的有效治疗。) 公共卫生相关性：脓毒症是一种多因素疾病，其潜在的病理生理机制尚不清楚;因此，寻求有效的挽救生命的治疗方法仍然难以捉摸。为了弥合小动物基础研究和临床研究之间的差距，本申请提出了使用与人类疾病相关的模型来研究抑制补体激活单独或作为组合疗法是否可以预防器官功能障碍并改善脓毒症的临床结果。由于与人类疾病的相似性，拟议的研究有可能促进将机制和疗法转化为临床，并导致真正的临床方法。)

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. )