Interleukin-1 Receptor Antagonist in ARDS

描述(申请人提供)：急性呼吸窘迫综合征(ARDS)是严重脓毒症的常见和破坏性并发症，具有非常高的死亡率。ARDS缺乏任何有效的药物治疗。我们之前描述了白介素1受体拮抗剂基因的一个功能性遗传变异，编码白介素1RA蛋白，它与降低ARDS风险、改善脓毒症存活率和升高血浆白介素1RA有关。一种重组形式的IL1RA(Anakinra)已被建议作为一种可能的治疗严重脓毒症的方法，严重脓毒症是ARDS最常见的诱因，尽管其效果不大，而且缺乏anakinra反应的预测指标。我们的初步数据增加了阿纳金拉治疗ARDS的可能性。这项应用将解决阿纳金拉是否有希望作为ARDS的预防或治疗药物，以及阿纳金拉的反应是否可以通过遗传或分子图谱来预测。在目标1中，我们将使用解释每个血浆标志物大部分变异的辅助变量来推断早期血浆IL1RA水平与ARDS易感性的因果关系，以及白细胞介素1β(IL1？)与ARDS死亡率的因果关系。如果这些标记物似乎是导致ARDS或死亡率的原因，那么下一步合理的做法是以Anakinra为靶点。在目标2中，我们使用人类内毒素刺激炎症应激的模型来确定诱发性血浆IL1RA的功能遗传决定因素，并测试功能变异与脓毒症相关的ARDS的关联。在目标3中，我们对上一次Anakinra在严重脓毒症中的随机对照试验中储存的血浆进行了分子特征分析，以测试血浆细胞因子水平或基因是否可以确定Anakinra降低死亡率的患者亚组。这项建议使用3个新的人类群体来研究IL1RA在脓毒症相关ARDS中的作用：监测ARDS的严重脓毒症危重受试者的大量队列；给予静脉内毒素作为炎症应激刺激的实验性人类志愿者池；以及随机接受安慰剂或阿纳金纳治疗的严重脓毒症患者的完成临床试验人群。该项目的完成将产生关于重组IL1RA预防或治疗ARDS的潜在作用的新知识，并可能为未来个性化IL1RA治疗的测试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.