Interleukin-1 Receptor Antagonist in ARDS

描述（由申请人提供）：急性呼吸窘迫综合征（ARDS）是严重脓毒症的常见和毁灭性并发症，死亡率非常高。ARDS缺乏有效的药物治疗。我们先前描述了白细胞介素-1受体拮抗剂基因的功能性遗传变异，编码蛋白质IL 1 RA，其与降低ARDS风险、改善脓毒症存活率和较高的血浆IL 1 RA相关。重组形式的IL 1 RA（阿那白滞素）已被建议作为一种可能的治疗严重脓毒症，最常见的急性呼吸窘迫综合征的促发剂，虽然效果是温和的，阿那白滞素反应的预测缺乏。我们的初步数据表明阿那白滞素可能是治疗急性呼吸窘迫综合征的一种有用的治疗方法。本申请将讨论阿那白滞素是否可能显示出作为ARDS的预防剂或治疗的前景，以及是否可以通过遗传或分子谱预测对阿那白滞素的反应。在目标1中，我们将使用基因型作为解释每个血浆标记物的大部分方差的工具变量，推断早期血浆IL 1 RA水平与ARDS易感性的因果关系，以及白细胞介素-1 β（IL 1 RA）与ARDS死亡率的因果关系。如果这些标志物似乎是ARDS或死亡的原因，那么用阿那白滞素靶向它们是合乎逻辑的下一步。在目标2中，我们使用人内毒素模型刺激炎症应激来鉴定诱发血浆IL 1 RA的功能性遗传决定因素，并测试与脓毒症相关的ARDS相关的功能性变体。在目标3中，我们从分子水平上分析了储存于最近一次阿那白滞素治疗严重脓毒症随机对照试验中的血浆，以测试血浆细胞因子水平或基因型是否可以定义阿那白滞素降低死亡率的患者亚组。该提案使用3个新的人群来解决IL 1 RA在脓毒症相关的ARDS中的作用：监测ARDS的严重脓毒症的危重受试者的大队列;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那白滞素的严重脓毒症的已完成临床试验人群。该项目的完成将产生关于重组IL 1 RA预防或治疗ARDS的潜在作用的新知识，并可能为未来个性化IL 1 RA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.