Complement C5a in Human Sepsis

描述(申请人提供)：每年，危及生命的感染和败血症在美国人身上造成巨大的损失。尽管通常被认为是重症监护病房的一种疾病，但基于人口的估计表明，每年有多达50万名败血症患者在急诊科接受治疗。脓毒症的一个基石是广泛存在的促炎和抗炎机制的失调。其中，补体级联是很有意义的，很大程度上是因为针对其在脓毒症中的作用进行了大量的临床前治疗。在这第一次竞争性更新中，我们的总体目标仍然是更好地了解补体级联，特别是激活产物C5a，在危及生命的急性感染和败血症中。补体对于早期细菌检测、宿主信号和病原体根除至关重要。然而，在啮齿动物模型中存在着广泛的证据(在脓毒症患者中的证据要小得多)，它的失调可以导致病理性的体液和细胞效应，这实际上可能增加全身感染的致死率。针对C5a及其受体的新疗法正在开发中，但临床上对这一人群补体激活的了解令人惊讶地有限。我们此次更新的重点是在急诊科对严重败血症患者进行评估。我们特别提出了三个目标。首先，我们打算招募150名严重脓毒症患者和150名非脓毒症患者，确定产生显著C5a的临床和遗传危险因素，并将这些特征与临床病程相关联。这一目标将包括平行测量血液中性粒细胞C5a受体的表达。在第二个目标中，我们将检查细菌表面的特征，这些表面有助于或抑制感染期间补体的激活和C5a的产生。这项工作将包括宿主杀菌活性和C5a生成的新分析，并将从我们的第一个目标开始测量患者子集的功能。在我们的第三个目标中，我们将从一个完全不同的角度来解决C5a在细菌表面产生的问题，通过首次检查肾上腺髓质素途径和替代补体途径之间的串扰，这两个途径由补体调节蛋白因子H联系在一起，因子H最近被确定为一种肾上腺髓质素结合蛋白，对于肾上腺髓质素的全部血管平滑肌作用是必要的。这项工作最大限度地利用了PI越来越多地接触严重败血症患者的机会，以及他为这项工作组建的越来越多的多学科团队。

DESCRIPTION (provided by applicant): Life-threatening infections and sepsis take an enormous toll on Americans each year. Although often considered a disease of intensive care units, population-based estimates suggest as many as 500,000 septic patients are cared for in emergency departments annually. A cornerstone of sepsis is widespread dysregulation of pro- and anti-inflammatory mechanisms. Among these, the complement cascade is of significant interest, largely because of the multitude of preclinical therapies directed against its role in sepsis. In this first competing renewal, our overall goal remains to better understand the complement cascade, and specifically the activation product C5a, in acute life-threatening infection and sepsis. Complement is crucial for early bacterial detection, host signaling, and pathogen eradication. However, extensive evidence exists in rodent models (and to a much lesser degree in septic patients) that its dysregulation can lead to pathologic humoral and cellular effects which may actually increase the lethality of systemic infection. Novel therapies targeting both C5a and its receptors are in development, but clinical understanding of complement activation in this population is surprisingly limited. Our focus in this renewal is severely septic patients being evaluated in the emergency department. We specifically propose three aims. First, we intend to enroll 150 patients with severe sepsis and 150 patients with non-septic illness and to identify clinical and genetic risk factors for significant C5a production and to correlate these features with clinical course. This aim will include parallel measurement of blood neutrophil C5a receptor expression. In the second aim, we will examine the features of bacterial surfaces that contribute to or inhibit the activation of complement and the production of C5a during infection. The work will include novel assays of host bactericidal activity and C5a generation and will measure function in a subset of patients from our first aim. In our third aim, we will approach the problem of C5a generation on bacterial surfaces from an altogether different perspective, by examining for the first time crosstalk between the adrenomedullin pathway and the alternative complement pathway, which are linked by the complement regulatory protein Factor H, which has recently been identified as an adrenomedullin binding protein necessary for the full vascular smooth muscle effects of adrenomedullin. The work takes maximum advantage of the PI's increasing access to severely septic patients as well as a growing multidisciplinary team that he has assembled for the work.