The Complement System and Ischemic Acute Renal Failure

项目摘要 这项资助研究了补体系统在缺血性心脏病发展中的作用。 急性肾功能衰竭。我们发表的研究表明，补体激活 促进缺血/再灌注(I/R)后的肾脏损伤，并发生这种激活 主要通过另一种途径。近年来，出现了另一种途径 在许多不同的疾病中，多年来都是伤害的关键调解人。这个系统是 在快速清除入侵病原体方面有效，但对激活的控制不足 酶允许宿主细胞的炎性损伤。这笔赠款的主要假设是 缺氧通过近端改变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改变为 补体激活表型。一旦激活，替代途径就会触发 产生促炎信号，包括C3a、C5a、巨噬细胞炎症 蛋白-2(MIP-2)和角质形成细胞来源的趋化因子(KC)。为了检验这一假设，我们将 使用体内和体外模型来确定表面抑制的丧失是否 足以引起自发的替代途径激活，并且通过 在I/R(SA1)后，这种表面抑制作用消失。因子H是一种有效的替代途径 高浓度循环但不能阻止替代途径的抑制剂 某些疾病中的中介伤害。我们还将研究一种新的补充 将因子H靶向补体激活部位的抑制剂可防止病理改变 肾I/R后补体激活及其调节保护作用的因素 表面受内源性因子H(SA2)影响。最后，我们将研究通过哪些机制 肾小管间质的替代途径激活可引发广泛的炎症 响应(SA3)。 缺血性急性肾功能衰竭是急性肾功能衰竭最常见的原因之一， 与重症监护病房中50%以上的死亡率有关。一个 一些补体抑制剂已经上市，包括一种特定的补体抑制剂 我们实验室已经开发的替代途径和一种靶向的抑制剂 这是我们的一个合作者开发的另一种途径。建议数 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 治疗缺血性急性肾功能衰竭，以及扩大我们对 补体激活作为肾小管损伤后炎症的介质。项目叙事 缺血性急性肾功能衰竭是急性肾功能衰竭最常见的原因之一， 与重症监护病房中50%以上的死亡率有关。 研究表明，补体系统在肾脏内被激活 缺血症。拟议中的实验考察了 补体系统与肾脏。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 缺血性急性肾功能衰竭。

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.