Reconsidering the IL-1 axis in sepsis-associated ARDS

重新考虑败血症相关 ARDS 中的 IL-1 轴

基本信息

批准号：
9922370
负责人：
Nuala Jennings Meyer
金额：
$ 47.37万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922370
关键词：
Adipose tissue Admission activity Adult Respiratory Distress Syndrome Alleles American Attenuated Award Biological Markers Blood Cessation of life Clinical Clinical Data Clinical Markers Clinical Trials Code Controlled Environment Data Development Edema Endotoxins Epidemiologist Etiology Failure Funding Future Genes Genetic Genotype Goals Heterogeneity Hour Human Hypoxia Individual Inflammation Injury Interleukin-1 Interleukin-1 beta Intervention Intervention Trial Knowledge Life Link Lung Lung Compliance Manuscripts Measures Mechanical ventilation Messenger RNA Modeling Modernization Molecular Molecular Profiling Oxygen Pathway interactions Patients Perfusion Permeability Pharmaceutical Preparations Pharmacotherapy Physiological Placebos Plasma Plasma Proteins Play Population Prevention Prevention strategy Production Randomized Recombinants Research Personnel Risk Role Safety Sepsis Septic Shock Subgroup System Target Populations Techniques Testing Translating Transplantation Variant Ventilator Work anakinra cohort cytokine design genetic analysis genetic variant improved individualized prevention injured lung injury member mortality mortality risk multidisciplinary novel patient population personalized intervention precision medicine preclinical efficacy predictive modeling prevent protein expression septic targeted treatment tool translational scientist treatment effect treatment strategy

项目摘要

The acute respiratory distress syndrome (ARDS) is a life-threatening condition of airspace inflammation and edema causing severely low blood oxygen levels that may complicate up to 24% of ICU admissions for mechanical ventilation. Mortality remains above 35% and no prevention or pharmacotherapy options exist. We previously identified and replicated a functional genetic variant in the interleukin-1 receptor antagonist (IL1RA) gene, encoding the protein IL1RA, that was strongly associated with lower ARDS risk and higher evoked plasma IL1RA levels. We also demonstrated a causal role for plasma interleukin-1 beta (IL1), the molecule inhibited by IL1RA, in mortality from septic shock. Finally, in a subgroup of subjects randomized to receive recombinant human interleukin-1 receptor antagonist (rhIL1RA) or placebo for sepsis, we demonstrated significant heterogeneity in the mortality treatment effect of rhIL1RA that was predictable by plasma IL1RA concentration. Taken together, our data indicated that some patients may be genetically protected from ARDS via more efficient IL1RA production, suggesting that the drug rhIL1RA may be an effective prevention or treatment strategy. However, because we proved that the effect of rhIL1RA during sepsis is not uniform, the current application will obtain critical information about the causal contribution of plasma IL1RA and IL1to ARDS risk and death from ARDS, will develop predictive models for ARDS risk in an effort to identify a target population for rhIL1RA intervention, and will determine the direct effects of rhIL1RA treatment on ex vivo perfused human lungs. Our long term objective is to evaluate rhIL1RA as a precision ARDS prevention and/or treatment strategy. Aim 1 will focus on ARDS risk, using a genetic instrumental variable technique to infer the causal effect of plasma IL1RA and IL1for ARDS risk, and developing and validating an ARDS predictive model that considers clinical factors and plasma IL-1 markers in 2 large sepsis cohorts. Aim 2 will focus on ARDS and sepsis mortality. We will use multiple genotypes as an instrumental variable to test the contribution of early or delayed plasma IL-1 markers for death from ARDS, and will develop and validate predictive models for ARDS mortality, using clinical data and plasma IL-1 markers measured in 2 large sepsis cohorts. In Aim 3, we will use a novel platform known as ex vivo lung perfusion (EVLP), whereby lungs declined for transplantation are ventilated and perfused in a highly controlled environment, to test whether rhIL1RA given as treatment or prevention to injured human lungs will improve oxygenation, lung compliance, and inflammation. The multidisciplinary team of investigators and consultants to enact these aims include an EVLP expert, 2 epidemiologists with expertise in lung injury prediction and molecular subphenotyping, a statistical geneticist who is expert in instrumental variable analysis, and the PI, a translational scientist who first identified a link between IL1RN variation, plasma protein expression, and ARDS risk.

急性呼吸窘迫综合征（ARDS）是空域注射和水肿导致严重低血氧水平，可补充多达24％的ICU入院机械通气。死亡率仍高于35％，没有预防或药物治疗方案。我们先前鉴定并复制了白介素-1受体拮抗剂（IL1RA）中的功能性遗传变异编码蛋白质IL1RA的基因与较低的ARDS风险密切相关，并唤起较高血浆IL1RA水平。我们还证明了血浆白介素-1β（IL1）的因果作用，分子被IL1RA抑制，因败血性休克而死亡。最后，在随机接收的受试者子组中重组人白细胞介素-1受体拮抗剂（Rhil1ra）或安慰剂用于败血症，我们证明了血浆IL1RA可预测的Rhil1RA死亡率治疗效应的显着异质性专注。综上所述，我们的数据表明某些患者可以受到遗传保护通过更有效的IL1RA生产，表明该药物Rhil1ra可能是有效的预防或治疗策略。但是，因为我们证明了败血症期间rhil1ra的作用并不统一，所以当前的应用将获得有关等离子体IL1RA和IL1的因果贡献的关键信息 ARDS的风险和ARDS死亡将开发针对ARDS风险的预测模型，以确定目标 RHIL1RA干预的种群，并将确定Rhil1ra治疗对离体的直接影响灌注的人肺。我们的长期目标是评估Rhil1ra作为预防和/或治疗策略。 AIM 1使用遗传仪器变量技术来推断ARDS风险等离子体IL1RA和IL1的因果效应，以产生ARDS风险，并发展和验证ARDS预测性模拟了在2个大型败血症队列中考虑临床因素和血浆IL-1标记的模型。 AIM 2将重点关注 ARDS和败血症死亡率。我们将使用多种基因型作为仪器变量来测试贡献 ARDS死亡的早期或延迟等离子体IL-1标记，并将开发和验证预测模型对于ARDS死亡率，使用临床数据和等离子IL-1标记在2个大型败血症同类中测得的。在AIM 3中，我们将使用一个名为Ex Vivo肺部灌注（EVLP）的新型平台，肺部下降了移植在高度控制的环境中通风和灌注，以测试Rhil1ra是否给予由于对受伤的人肺的治疗或预防将改善氧合，肺合顺顺和炎。颁布这些目标的调查人员和顾问的多学科团队包括EVLP 专家，2名具有肺损伤预测专家的流行病学家和分子亚型型，统计是仪器变量分析专家的通用者，而PI是翻译科学家，他首先确定 IL1RN变异，血浆蛋白表达和ARDS风险之间的联系。