Evaluation of alternative complement activity within an ARDS cohort

项目概述：补体途径，特别是替代补体（AP）途径，是一种 一种古老的免疫监视系统，是作为一种消除病原体或细胞碎片的机制而发展起来的， 特异性免疫反应的发展。这条通路有其自身激活的“内置”调节器， 防止附带组织损伤，以及可能导致通路的正臂和负臂的不平衡 在严重的疾病中附带的组织损伤该应用程序的目标是利用现有的 储存在NHLBI生物标本库中的生物标本采集，并测试是否有替代品 补体途径（AP）活性和旁路途径的关键成分预测总生存率， ARDS患者。我们建议使用从入组Lisofylline的受试者获得的血清样本， 测定AP活性并探索补体因子B（CF B）平衡的ALI/ARDS试验（LARMA）研究 AP激活的重要近端介质，以及AP激活的负调节因子CFH水平。我们也 建议使用他汀类药物治疗脓毒症所致急性肺损伤试验入组受试者的血浆样本 （SAILS）评估CFB和CFH水平的平衡以及与炎症和死亡率的相关性。我们 来自急性呼吸道疾病的重症机械通气患者的单中心队列的初步数据 失败表明，较高的AP活性，但不是经典的补体途径活性，与降低的 全因死亡率AP功能增强与血流感染风险降低相关，血清 来自具有增强的AP功能的个体显示出显著抑制广泛耐药的能力， 产碳青霉烯酶肺炎克雷伯菌体外生长。此外，增加的AP功能是 与较高的CFB和CFH水平相关，较高的CFB和CFH水平均预测生存率提高。 主要假设是旁路途径活性（AH 50）和AP的关键组分预测总体 通过BioLINCC获得的两项多中心、随机、前瞻性试验中ARDS患者的生存率。 目的1将检测AP活性、CFB和CFH水平与患者28天死亡率风险之间的关系 加入LARMA。作为次要终点，我们将检验AP活性与无呼吸机 天，在原始LARMA研究中检查的五个非肺器官的无器官衰竭天数。目的2 将确定CFB和CFH水平是否预测脓毒症相关急性肺损伤队列的死亡率。 作为次要终点，我们将检查CFB、CFH水平与无呼吸机天数之间的关系， 无器官衰竭天数和通过C反应蛋白测量的全身炎症 队列。了解免疫激活和调节因子的平衡是迈向 未来临床试验的设计和拟议工作的成功完成可能为以下方面提供新的机会： 针对重症监护环境中获得性AP补体缺乏症患者的靶向治疗。

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.