Complement C5a in Human Sepsis

补体 C5a 在人类脓毒症中的作用

• 批准号: 8041457
• 负责人: JOHN G YOUNGER
• 金额: $ 42.93万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8041457
• 关键词: Accident and Emergency department; Acute; Address; Age; Alternative Complement Pathway; American; Anti-Inflammatory Agents; Anti-inflammatory; Bacteria; Binding Proteins; Biological Assay; Blood Vessels; Body part; C5a anaphylatoxin receptor; Carbohydrates; Caring; Clinical; Communities; Complement; Complement 5a; Complement Activation; Complement Factor H; Complement Membrane Attack Complex; Critical Illness; Detection; Development; Diagnosis; Disease; Enrollment; Failure; Gender; Generations; Genetic; Goals; Healthcare Systems; Human; Immune system; Immunology; Individual; Infection; Inflammation; Inflammatory; Intensive Care Units; Laboratories; Lead; Leukocytes; Life; Link; Measurement; Measures; Mediating; Mediator of activation protein; Mind; Organism; Outcome; Pathologic; Pathway interactions; Patient Care; Patients; Phase; Population; Production; Race; Regulatory Pathway; Resuscitation; Rodent Model; Role; Science; Sepsis; Serum; Severities; Severity of illness; Signal Transduction; Source; Structure; Surface; System; Systemic infection; Time; Vascular Smooth Muscle; Work; activation product; adrenomedullin; bactericide; base; clinical research site; cohort; complement system; experience; genetic regulatory protein; genetic risk factor; interest; killings; multidisciplinary; neutrophil; novel; pathogen; pathogenic bacteria; population based; pre-clinical therapy; programs; receptor; receptor expression; response; septic

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. PUBLIC HEALTH RELEVANCE: The goal of this work is to better understand the role of the complement system (a part of the body's immune system) in the development and outcome of life-threatening infections in patients presenting to emergency departments. The program will include the enrollment of 300 seriously ill patients and will examine in the laboratory the function of their complement cascade in detail. Additional work will examine in detail the mechanism of complement activation on the surface of pathogenic bacteria as well as the interaction between the complement system and the adrenomedullin system, which has recently been recognized to share a common regulatory protein with the alternative pathway. Ultimately our hope is to recognize in which patients abnormal complement activation is occurring, understand the circumstances that have led to that response, and identify steps to reverse the harmful effects complement may be having in community- acquired critical illness.

描述（由申请人提供）：危及生命的感染和败血症每年给美国人带来巨大的损失。尽管通常被认为是重症监护病房的疾病，但基于人群的估计表明，每年有多达 500,000 名脓毒症患者在急诊科接受护理。脓毒症的一个基石是促炎和抗炎机制的广泛失调。其中，补体级联反应引起了人们的极大兴趣，这主要是因为大量的临床前治疗针对其在脓毒症中的作用。在这第一次竞争更新中，我们的总体目标仍然是更好地了解急性危及生命的感染和败血症中的补体级联，特别是激活产物 C5a。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，啮齿动物模型中存在大量证据（脓毒症患者的程度要小得多），表明其失调可能导致病理性体液和细胞效应，这实际上可能会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，但对该人群中补体激活的临床了解却非常有限。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 名严重脓毒症患者和 150 名非脓毒症患者，以确定 C5a 显着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。该目标将包括并行测量血液中性粒细胞 C5a 受体表达。在第二个目标中，我们将研究感染期间有助于或抑制补体激活和 C5a 产生的细菌表面特征。这项工作将包括对宿主杀菌活性和 C5a 生成的新测定，并将根据我们的首要目标测量一部分患者的功能。在我们的第三个目标中，我们将从一个完全不同的角度解决细菌表面 C5a 生成的问题，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，这两种途径通过补体调节蛋白 H 因子连接，最近已被鉴定为肾上腺髓质素的全血管平滑肌作用所必需的肾上腺髓质素结合蛋白。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的机会，以及他为这项工作组建的不断壮大的多学科团队。 公共卫生相关性：这项工作的目标是更好地了解补体系统（身体免疫系统的一部分）在急诊室患者危及生命的感染的发展和结果中的作用。该计划将招募 300 名重病患者，并将在实验室详细检查他们的补体级联的功能。其他工作将详细研究病原菌表面补体激活的机制，以及补体系统和肾上腺髓质素系统之间的相互作用，最近人们认识到肾上腺髓质素系统与旁路途径共享共同的调节蛋白。最终，我们的希望是认识到哪些患者正在发生补体异常激活，了解导致这种反应的情况，并确定采取措施扭转补体可能对社区获得性危重疾病产生的有害影响。