Interleukin-1 Receptor Antagonist in ARDS

描述（由申请人提供）：急性呼吸窘迫综合征（ARDS）是严重败血症的常见和破坏性并发症，具有很高的死亡率。ARDS缺乏有效的药物治疗。我们之前描述了白细胞介素-1受体拮抗剂基因的功能遗传变异，编码蛋白IL1RA，与降低ARDS风险，改善败血症存活率和提高血浆IL1RA相关。重组形式的IL1RA （anakinra）已被建议作为严重脓毒症（ARDS最常见的诱因）的可能治疗方法，尽管效果一般，且缺乏anakinra反应的预测因子。我们的初步数据表明，阿那白可能是治疗ARDS的有效方法。这项应用将探讨安纳那白素是否有希望作为ARDS的预防药物或治疗药物，以及安纳那白素的反应是否可以通过基因或分子谱来预测。在目的1中，我们将推断早期血浆IL1RA水平与ARDS易感性的因果关系，以及白细胞介素-1 β （IL1ß）与ARDS死亡率的因果关系，使用基因型作为解释每种血浆标志物方差的很大一部分的工具变量。如果这些标记似乎是ARDS或死亡率的原因，那么用anakinra靶向它们是合乎逻辑的下一步。在目的2中，我们使用人内毒素模型来刺激炎症应激，确定诱发血浆IL1RA的功能遗传决定因素，并测试与败血症相关ARDS相关的功能变异。在目的3中，我们对阿那白那在严重脓毒症中的最后一次随机对照试验中储存的血浆进行了分子表征，以测试血浆细胞因子水平或基因型是否可以定义阿那白那降低死亡率的患者亚组。本研究使用3个新的人群来研究IL1RA在脓毒症相关ARDS中的作用：一组监测严重脓毒症的危重患者；一个实验人类志愿者池给予静脉内毒素作为炎症应激的刺激；一组完成临床试验的严重败血症患者被随机分为安慰剂组和阿那白组。该项目的完成将产生关于重组IL1RA在预防或治疗ARDS中的潜在作用的新知识，并可能为未来测试个性化IL1RA治疗确定理想的临床试验人群。

DESCRIPTION (provided by applicant): The acute respiratory distress syndrome (ARDS) is a common and devastating complication of severe sepsis carrying a very high mortality. ARDS lacks any effective pharmacotherapy. We previously described a functional genetic variant in the interleukin-1 receptor antagonist gene, encoding the protein IL1RA, which associates with reduced ARDS risk, improved sepsis survival, and with higher plasma IL1RA. A recombinant form of IL1RA (anakinra) has been suggested as a possible therapy for severe sepsis, the most common precipitant of ARDS, though the effect was modest and predictors of anakinra response are lacking. Our preliminary data raises the possibility that anakinra would be a helpful therapy in ARDS. This application will address whether anakinra may show promise as a preventative agent or a therapy in ARDS and whether response to anakinra may be predicted by genetic or molecular profiles. In aim 1, we will infer the causality of early plasma IL1RA level for ARDS susceptibility, and the causality of interleukin-1 beta (IL1ß) for ARDS mortality, using genotype as an instrumental variable that explains a large proportion of each plasma marker's variance. If these markers seem to be causal for ARDS or mortality, then targeting them with anakinra is a logical next step. In aim 2, we identify the functional genetic determinants of evoked plasma IL1RA using a human endotoxin model to stimulate inflammatory stress, and test functional variants for association with sepsis-associated ARDS. In aim 3, we molecularly characterize plasma stored from the last randomized controlled trial of anakinra in severe sepsis, to test whether plasma cytokine level or genotype can define a subgroup of patients who had reduced mortality with anakinra. This proposal uses 3 novel human populations to address the role of IL1RA in sepsis-associated ARDS: a large cohort of critically ill subjects with severe sepsis monitored for ARDS; an experimental human volunteer pool given intravenous endotoxin as a stimulus for inflammatory stress; and a completed clinical trial population with severe sepsis who were randomized to receive placebo or anakinra. Completion of this project will yield new knowledge regarding the potential role of recombinant IL1RA to prevent or treat ARDS, and may identify an ideal clinical trial population for future testing of personalized IL1RA therapy.