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: 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
• 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

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)是一种危及生命的空域炎症和 浮肿导致严重的低血氧水平，可能会使高达24%的ICU入院人数复杂化 机械通风。死亡率保持在35%以上，没有预防或药物治疗的选择。我们 以前发现并复制了白细胞介素1受体拮抗剂(IL1RA)中的一个功能性遗传变体 编码IL1RA蛋白的基因，与较低的ARDS风险和较高的诱发性密切相关 血浆IL1RA水平。我们还证明了血浆白介素1β(IL1)的因果作用。 IL1RA抑制败血症休克死亡率。最后，在随机接受的一组受试者中 重组人白介素1受体拮抗剂(RhIL1RA)或安慰剂治疗脓毒症 血浆IL-1RA可预测的重组人IL-1RA死亡率治疗效果的显著异质性 集中精神。总而言之，我们的数据表明，一些患者可能在基因上受到保护，不受ARDS的影响 通过更高效地产生IL1RA，提示药物rhIL1RA可能是一种有效的预防或 治疗策略。然而，由于我们证明了rhIL1RA在脓毒症中的作用并不是一致的，所以 目前的应用将获得有关血浆IL1RA和IL1的因果贡献的关键信息 ARDS风险和ARDS死亡，将开发ARDS风险的预测模型，以努力确定目标 对重组人白细胞介素1RA进行干预，并将确定重组人白细胞介素1RA治疗对体外的直接影响 灌流的人肺。我们的长期目标是评估重组人白介素1RA作为一种精确的ARDS预防和/或 治疗策略。目标1将专注于ARDS风险，使用遗传工具变量技术来推断 血浆白介素1RA和白介素1与急性呼吸窘迫综合征风险的因果关系及急性呼吸窘迫综合征预测的建立和验证 在两个大型脓毒症队列中考虑临床因素和血浆IL-1标志物的模型。《目标2》将专注于 急性呼吸窘迫综合征和败血症死亡率。我们将使用多种基因类型作为工具变量来测试贡献 ARDS死亡的早期或延迟血浆IL-1标志物的研究，并将开发和验证预测模型 对于ARDS死亡率，使用临床数据和在2个大型脓毒症队列中测量的血浆IL-1标记物。在《目标3》中， 我们将使用一种名为体外肺灌注(EVLP)的新平台，通过该平台，肺功能下降 移植在高度受控的环境中进行通风和灌流，以测试是否给予重组人白细胞介素1RA 因为对受伤的人肺的治疗或预防将改善氧合，肺顺应性，以及 发炎。实施这些目标的多学科调查员和顾问团队包括一个EVLP 专家，2名流行病学家，具有肺损伤预测和分子亚型方面的专业知识， 遗传学家，他是工具变量分析方面的专家，PI，一位翻译科学家，他最先发现了 IL1RN变异、血浆蛋白表达和ARDS风险之间的联系。