The Complement System and Ischemic Acute Renal Failure

补体系统与缺血性急性肾衰竭

• 批准号: 8287074
• 负责人: Joshua M Thurman
• 金额: $ 30.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287074
• 关键词: Acute Kidney Failure; Aftercare; Age related macular degeneration; Agonist; Alternative Complement Pathway; Annexins; Antibodies; Apoptosis; Binding; Biological Assay; Bypass; C3bi; Cell Surface Receptors; Cell surface; Cells; Chemicals; Complement; Complement 3a; Complement 3b; Complement 3b Inactivators; Complement 3d Receptors; Complement 5a; Complement Activation; Complement Factor B; Complement Factor H; Complement Inactivators; Complement Receptor; Complex; Crying; Cytolysis; Data; Deposition; Development; Disease; Dominant-Negative Mutation; Endogenous Factors; Enzyme-Linked Immunosorbent Assay; Enzymes; Epithelial Cells; Gene Proteins; Generations; Grant; Hemolytic-Uremic Syndrome; Histologic; Human; Hypoxia; Immunofluorescence Immunologic; Immunofluorescence Microscopy; In Vitro; Incubated; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Intensive Care Units; Ischemia; Kidney; Laboratories; Measurement; Measures; Mediating; Mediator of activation protein; Methods; Mus; Neutrophil Infiltration; Pathologist; Pathway interactions; Phenotype; Plasma; Plasminogen; Production; Proteins; Publishing; Recovery; Regulation; Reperfusion Therapy; Role; Serum; Signal Transduction; Site; Surface; System; TLR2 gene; TLR4 gene; Testing; Therapeutic Agents; Thromboplastin; Time; Tissues; Toll-like receptors; Transfection; Treatment Efficacy; Tubular formation; Urea Nitrogen; Western Blotting; Work; cell injury; chemokine; complement system; cytotoxic; cytotoxicity; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; keratinocyte; macrophage inflammatory protein 2; mortality; novel; novel therapeutics; pathogen; prevent; protein expression; receptor; reconstitution; renal ischemia; research study; response; sample fixation

Project Summary This grant examines the role of the complement system in the development of ischemic acute renal failure. Our published work demonstrates that complement activation contributes to renal injury after ischemia/reperfusion (I/R), and that activation occurs primarily through the alternative pathway. The alternative pathway has emerged, in recent years, as a critical mediator of injury in a number of different diseases. This system is effective at rapidly eliminating invasive pathogens, but insufficient control of the activating enzymes permits inflammatory injury of host cells. The primary hypothesis of this grant is that hypoxia alters the surface expression of complement inhibitory proteins by proximal tubular epithelial cells. This changes the cells from a complement inhibitory to a complement activating phenotype. Once activated, the alternative pathway triggers generation of pro-inflammatory signals, including C3a, C5a, macrophage inflammatory protein-2 (MIP-2) and keratinocyte derived chemokine (KC). To test this hypothesis we will use in vivo and in vitro models to determine whether the loss of surface inhibition is sufficient to cause spontaneous alternative pathway activation, and the mechanisms by which this surface inhibition is lost after I/R (SA1). Factor H is a potent alternative pathway inhibitor that circulates in high concentrations but fails to prevent alternative pathway mediated injury in certain diseases. We will also examine whether a novel complement inhibitor that targets factor H to the site of complement activation prevents pathological complement activation after renal I/R, and the factors that modulate protection of this surface by endogenous factor H (SA2). Finally, we will examine the mechanisms by which alternative pathway activation in the tubulointerstitium triggers a widespread inflammatory response (SA3). Ischemic acute renal failure is one of the most common causes of acute renal failure, and is associated with a mortality rate of greater than 50% in the intensive care unit setting. A number of complement inhibitors have become available, including a specific inhibitor of the alternative pathway that has been developed by our laboratory and a targeted inhibitor of the alternative pathway that was developed by one of our collaborators. The proposed studies should help delineate the benefits and limitations of complement inhibition as a therapy for ischemic acute renal failure, as well as expand our understanding of complement activation as a mediator of inflammation after renal tubular injury. PROJECT NARRATIVE Ischemic acute renal failure is one of the most common causes of acute renal failure, and is associated with a mortality rate of greater than 50% in the intensive care unit setting. Studies have demonstrated that the complement system is activated within the kidney after ischemia. The proposed experiments examine the complex interactions between the complement system and the kidney. These studies will identify therapies that effectively inhibit the complement system and determine whether these agents will ameliorate ischemic acute renal failure.

项目摘要 该基金研究了补体系统在缺血性心脏病发展中的作用。 急性肾衰竭我们发表的工作表明，补体激活 导致缺血/再灌注（I/R）后的肾损伤，并发生激活 主要是通过替代途径。替代途径已经出现，最近， 多年来，作为一个重要的调解人的伤害，在一些不同的疾病。该系统 有效地迅速消除入侵病原体，但对激活的 酶允许宿主细胞的炎性损伤。这项补助金的主要假设是 缺氧改变了补体抑制蛋白的表面表达， 肾小管上皮细胞这将细胞从补体抑制性变为补体抑制性。 补体激活表型一旦被激活，替代途径就会触发 产生促炎信号，包括C3 a、C5 a、巨噬细胞炎性 蛋白-2（MIP-2）和角质形成细胞衍生的趋化因子（KC）。为了验证这个假设，我们将 使用体内和体外模型来确定表面抑制的丧失是否 足以引起自发的旁路途径激活，以及通过 在I/R（SA 1）之后，该表面抑制消失。因子H是一种有效的替代途径 以高浓度循环但不能阻止旁路途径的抑制剂 在某些疾病中介导损伤。我们还将研究一个新的补语是否 将因子H靶向补体激活位点的抑制剂可防止病理性 肾I/R后补体激活，以及调节这种保护的因素 内源性H因子（SA 2）。最后，我们将研究 肾小管上皮细胞中的旁路途径激活引发了广泛的炎症反应， 反应（SA 3）。 缺血性急性肾衰竭是急性肾衰竭最常见的原因之一， 与重症监护病房中超过50%的死亡率相关。一 许多补体抑制剂已经变得可用，包括一种特异性补体抑制剂。 替代途径，已经开发了我们的实验室和靶向抑制剂， 我们的一位合作者开发的替代途径。拟议 研究应该有助于描述补体抑制作为一种治疗方法的益处和局限性。 治疗缺血性急性肾衰竭，以及扩大我们的理解， 补体激活作为肾小管损伤后炎症介质。项目叙述 缺血性急性肾衰竭是急性肾衰竭最常见的原因之一， 与重症监护病房中超过50%的死亡率相关。 研究已经证明，补体系统在肾脏内被激活后， 缺血拟议的实验研究了 补体系统和肾脏。这些研究将确定有效的治疗方法， 抑制补体系统，并确定这些药物是否会改善 缺血性急性肾衰竭