Reconsidering the IL-1 axis in sepsis-associated ARDS

重新考虑败血症相关 ARDS 中的 IL-1 轴

• 批准号: 9364772
• 负责人: Nuala Jennings Meyer
• 金额: $ 53.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9364772
• 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; 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

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）是一种危及生命的气道炎症， 水肿导致严重的低血氧水平，可能使24%的ICU入院复杂化， 机械通气死亡率仍然高于35%，没有预防或药物治疗方案。我们 先前在白细胞介素-1受体拮抗剂（IL 1 RA）中鉴定并复制了一种功能性遗传变体 编码蛋白质IL 1 RA的基因与较低的ARDS风险和较高的诱发性呼吸窘迫综合征密切相关 血浆IL 1 RA水平。我们还证明了血浆白细胞介素-1 β（IL 1 β）的因果作用， IL-1 RA抑制的感染性休克的死亡率。最后，在一个随机接受 重组人白细胞介素1受体拮抗剂（rhIL 1 RA）或安慰剂治疗脓毒症，我们证明， rhIL 1 RA的死亡率治疗效应具有显著异质性，可通过血浆IL 1 RA预测 浓度.总之，我们的数据表明，一些患者可能是遗传保护，从ARDS 通过更有效的IL 1 RA生产，这表明药物rhIL 1 RA可能是一种有效的预防或 治疗策略然而，由于我们证明了rhIL 1 RA在脓毒症中的作用是不均匀的， 本申请将获得关于血浆IL 1 RA和IL 1 β的因果作用的关键信息， ARDS风险和ARDS死亡，将开发ARDS风险的预测模型，以确定目标 人群进行rhIL 1 RA干预，并将确定rhIL 1 RA治疗对离体 灌注的人肺我们的长期目标是评估rhIL 1 RA作为一种精确的ARDS预防和/或 治疗策略目标1将集中于ARDS风险，使用遗传工具变量技术来推断 血浆IL-1 RA和IL-1 β对ARDS风险的因果作用，以及开发和验证ARDS预测因子 该模型考虑了2个大型脓毒症队列中的临床因素和血浆IL-1标志物。目标2将侧重于 ARDS和脓毒症死亡率。我们将使用多个基因型作为工具变量来测试贡献 早期或延迟血浆IL-1标记物对ARDS死亡的预测，并将开发和验证预测模型 对于ARDS死亡率，使用2个大脓毒症队列中测量的临床数据和血浆IL-1标志物。在目标3中， 我们将使用一种称为离体肺灌注（EVLP）的新平台， 在高度受控的环境中进行通气和灌注，以测试rhIL 1 RA是否被给予 因为对受伤的人肺的治疗或预防将改善氧合、肺顺应性， 炎症制定这些目标的多学科调查人员和顾问小组包括一个EVLP 专家，2名流行病学家，具有肺损伤预测和分子亚表型方面的专业知识， 遗传学家谁是专家在工具变量分析，和PI，一个翻译科学家谁第一次发现 IL 1 RN变异、血浆蛋白表达和ARDS风险之间的联系。