Evaluation of alternative complement activity within an ARDS cohort

ARDS 队列中替代补体活性的评估

• 批准号: 10231193
• 负责人: Seyed Mehdi Nouraie
• 金额: $ 12.43万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-09 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231193
• 关键词: Acute; Acute Lung Injury; Acute respiratory failure; Adult Respiratory Distress Syndrome; Alternative Complement Pathway; Anaphylatoxins; Antibodies; Biological Assay; Biological Markers; Biological Specimen Banks; C-reactive protein; Carbohydrates; Cells; Cessation of life; Clinical; Clinical Trials; Clinical Trials Design; Collection; Complement; Complement 3; Complement 3 Convertase; Complement 3b; Complement Activation; Complement Factor B; Complement Factor H; Complement Membrane Attack Complex; Complication; Critical Care; Critical Illness; Cytolysis; Data; Development; Diffuse; Economic Burden; Edema; Enrollment; Enzyme-Linked Immunosorbent Assay; Equilibrium; Evaluation; Future; Goals; Growth; Heart failure; Hospitalization; Host Defense; Humoral Immunities; Hydrolysis; Immune; Immune response; Immunity; Immunologic Surveillance; In Vitro; Individual; Infection; Inflammation; Inflammatory Response; Klebsiella pneumoniae; Lectin; Length; Life; Link; Lisofylline; Lung; Mannose Binding Lectin; Measures; Mechanical ventilation; Mediator of activation protein; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Organ; Organ failure; Pathway interactions; Patients; Phagocytosis; Phenotype; Plasma; Pneumonia; Randomized; Risk; Risk Factors; Sampling; Sepsis; Serum; Surface; System; Testing; Ticks; Tissues; Ventilator; Work; antigen binding; arm; cell injury; cohort; complement deficiency; complement pathway; complement system; design; extensive drug resistance; immune activation; improved; microbial; microbial host; mortality; outcome prediction; pathogen; prevent; prospective; resilience; secondary endpoint; survival prediction; systemic inflammatory response; targeted treatment

Project Summary: The complement pathway, particularly the alternative complement (AP) pathway, is an ancient immune surveillance system developed as a mechanism to eliminate pathogen or cellular debris before the development of specific immune responses. This pathway has ‘built-in’ regulators of its own activation that prevent collateral tissue damage, and the imbalance of the positive and negative arms of the pathway may result in collateral tissue damage during profound illness. The goal of this application is to utilize the existing biospecimen collection that are stored in the NHLBI Biologic Specimen Repository and test whether alternative complement pathway (AP) activity and key components of the alternative pathway predict overall survival in patients with ARDS. We propose to use serum samples available from subjects enrolled in the Lisofylline for ALI/ARDS trial (LARMA) study to determine AP activity and explore the balance of complement factor B (CFB) an essential proximal mediator of AP activation, and CFH, a negative regulator of AP activation, levels. We also propose to use plasma samples from subjects enrolled in the Statins for Acutely Injured Lungs from Sepsis trial (SAILS) to assess the balance of CFB and CFH levels and association with inflammation and mortality. Our preliminary data from a single center cohort of critically ill mechanically ventilated patients with acute respiratory failure show that higher AP activity, but not classical complement pathway activity, is associated with reduced all-cause mortality. Enhanced AP function is associated with reduced risk of bloodstream infection, and serum from individuals with enhanced AP function show ability to substantially inhibit extensively-drug resistant carbepenemase-producing Klebsiella pneumoniae growth in vitro. Moreover, increased AP function is associated with higher CFB and CFH levels and both higher CFB and CFH levels predict enhanced survival. The major hypothesis is that alternative pathway activity (AH50) and key components of AP predict overall survival in patients with ARDS from two multi-center, randomized, prospective trials available through BioLINCC. Aim 1 will test the association between AP activity, CFB and CFH levels, and risk of 28-day mortality in patients enrolled in LARMA. As secondary endpoints, we will test the relationship between AP activity and ventilator-free days, organ failure-free days for the five non-pulmonary organs examined in the original LARMA study. Aim 2 will identify whether CFB and CFH levels predict mortality in a cohort with sepsis-associated acute lung injury. As secondary endpoints, we will examine the relationship between CFB, CFH levels and ventilator-free days, organ-failure free days, and systemic inflammation as measured by C-reactive protein in the original SAILS cohort. Understanding the balance of immune activation and regulatory factors is an important step toward design of future clinical trials and successful completion of the work proposed may provide new opportunities for targeting therapy to those with acquired AP complement deficiency in the critical care setting.

项目摘要：完成途径，尤其是替代完成（AP）途径，是一个 古老的免疫外科系统发展为消除病原体或细胞碎屑之前的机制 特定免疫反应的发展。该途径具有其自身激活的“内置”调节器 防止侧支组织损伤，并且可能导致途径正面和负臂的失衡 在严重疾病期间的附带组织损害中。此应用程序的目的是利用现有的 存储在NHLBI Biologic标本存储库中的生物测量集合并测试是否替代 补体途径（AP）活性和替代途径的关键组成部分预测了总体生存 ARDS患者。我们建议使用在Lisofylline入学的受试者中可用的血清样本 ALI/ARDS试验（LARMA）研究以确定AP活性并探索补体因子B（CFB）的平衡 AP激活的基本近端介体和AP激活的负调节剂CFH水平。我们也是 建议使用他汀类药物入学的受试者的血浆样品，以急性损伤败血症试验 （帆）评估CFB和CFH水平的平衡以及与创新和死亡率的关联。我们的 来自单个中心队列的初步数据，急性呼吸道疾病的患者机械通风患者 故障表明，较高的AP活动（而不是经典的补体途径活动）与减少有关 全因死亡率。增强的AP功能与降低血液感染的风险和序列化有关 来自具有增强AP功能的个体显示出实质上抑制广泛抗药性的能力 体外产生卡蛋白酶产生克雷伯菌肺炎的生长。而且，增加的AP功能是 与较高的CFB和CFH水平以及CFB和CFH水平较高有关，可以预测生存率增强。 主要的假设是替代途径活动（AH50）和AP的关键组成部分预测了总体 通过Biolincc获得的两个多中心，随机的前瞻性试验的ARDS患者的存活率。 AIM 1将测试AP活动，CFB和CFH水平之间的关联，并在患者中死亡28天死亡率 在拉尔玛（Larma）注册。作为次要终点，我们将测试AP活动与无呼吸机之间的关系 天数，在原始LARMA研究中检查的五个非肺部器官的无器官衰竭天数。目标2 将确定CFB和CFH水平是否可以预测与败血症相关急性肺损伤的队列中死亡率。 作为次要终点，我们将研究CFB，CFH级别和无呼吸机的关系之间的关系， 器官失效的日子和原始帆中C反应蛋白测量的全身性炎症 队列。了解免疫激活和调节因素的平衡是迈向的重要一步 设计未来的临床试验和成功完成的工作可能为您提供新的机会 针对在重症监护环境中获得AP完成缺陷的人的靶向治疗。

项目成果

Thrombospondin-1 Restricts Interleukin-36γ-Mediated Neutrophilic Inflammation during Pseudomonas aeruginosa Pulmonary Infection.

• DOI: 10.1128/mbio.03336-20
• 发表时间: 2021-04-06
• 期刊: mBio
• 影响因子: 6.4
• 作者: Peñaloza HF;Olonisakin TF;Bain WG;Qu Y;van der Geest R;Zupetic J;Hulver M;Xiong Z;Newstead MW;Zou C;Alder JK;Ybe JA;Standiford TJ;Lee JS
• 通讯作者: Lee JS