Complement C5a in Human Sepsis

描述（由申请人提供）：危及生命的感染和败血症每年对美国人造成巨大损失。虽然通常被认为是重症监护病房的疾病，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室接受治疗。脓毒症的基础是促炎和抗炎机制的广泛失调。其中，补体级联是重要的兴趣，主要是因为针对其在脓毒症中的作用的大量临床前治疗。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反应，特别是活化产物C5a，在急性危及生命的感染和败血症中。补体对于早期细菌检测、宿主信号传导和病原体根除至关重要。然而，在啮齿类动物模型中存在大量证据（在脓毒症患者中的程度要小得多），其失调可导致病理性体液和细胞效应，这实际上可能增加全身感染的致死率。靶向C5a及其受体的新疗法正在开发中，但对该人群中补体激活的临床理解令人惊讶地有限。我们这次更新的重点是在急诊室接受评估的严重脓毒症患者。我们具体提出三个目标。首先，我们打算招募150例严重脓毒症患者和150例非脓毒症患者，并确定显著C5a产生的临床和遗传风险因素，并将这些特征与临床病程相关联。该目的将包括血液中性粒细胞C5a受体表达的平行测量。在第二个目标中，我们将研究细菌表面的特征，这些特征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生成的新测定，并将测量我们第一个目标的一部分患者的功能。在我们的第三个目标中，我们将从一个完全不同的角度来探讨细菌表面产生C5a的问题，通过检查肾上腺髓质素途径和替代补体途径之间的第一次串扰，这是由补体调节蛋白H因子，最近已被确定为肾上腺髓质素结合蛋白所必需的肾上腺髓质素的完整的血管平滑肌效应。这项工作最大限度地利用了PI越来越多地接触严重脓毒症患者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.