The Inflammasome: A Novel Biomarker in ALI/ARDS

炎症小体：ALI/ARDS 的新型生物标志物

基本信息

批准号：
8830994
负责人：
Rebecca M Baron
金额：
$ 43.33万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8830994
关键词：
Acute Acute Lung Injury Address Adult Respiratory Distress Syndrome Ancillary Study Animals Anti-Inflammatory Agents Anti-inflammatory Apoptosis Autophagocytosis Bacterial Infections Biological Markers Biomedical Research Blood C-terminal Caspase Caspase-1 Cells Cellular Stress Clinical Clinical Trials Collaborations Collection Complex Critical Illness Data Development Diagnostic Enrollment Family Gene Expression Gene Proteins Human Immune response Infection Inflammation Inflammatory Inflammatory Response Interleukin-18 Interleukins Lung Inflammation Mediating Mitochondria Modeling Mus Outcome Patients Placebos Plasma Play Process Proteins Reporting Research Personnel Respiratory Failure Risk Factors Role Sampling Seminal Sepsis Severities Severity of illness Signal Pathway Signal Transduction Source Stress Toll-like receptors Tumor Necrosis Factor-alpha Up-Regulation cytokine extracellular human disease interest lung injury member microorganism mitochondrial dysfunction monocyte mortality neutrophil novel pathogen protein complex randomized trial receptor response response to injury secondary outcome therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The inflammasome has recently been described as an important protein complex in which a non-NFkB- mediated signaling pathway leads to up-regulation of key pro-inflammatory cytokines, including interleukin (IL)- 1b and IL-18. Members of our group recently reported that the inflammasome plays a critical role in pro- inflammatory response in murine sepsis, and this response is dependent upon mitochondrial integrity and an intact autophagy response to injury. We now present data supporting an important role for the inflammasome in predicting severity and mortality during human infection-related ALI/ARDS. Moreover, our preliminary animal studies demonstrate that statins exacerbate lung injury and inflammation via activation of the inflammasome. We therefore hypothesize that activation of the inflammasome plays a critical role in the development of infection-related ALI/ARDS and that statin administration may increase inflammasome-related downstream cytokines during lung injury. In particular, our collaboration with the ARDSnet SAILS trial investigators (a randomized trial of statins vs. placebo in infection-related ALI/ARDS) in this Ancillary Studies in Clinical Trials RFA (HL-12-012) provides a unique opportunity to obtain additional collection of key human samples to address these important processes. We therefore propose: Specific Aim 1: To determine gene expression and protein levels of the inflammasome during infection-related ALI/ARDS using prospectively collected blood (n=100) and banked plasma samples (n=600) from placebo- and statin-treated SAILS subjects. Gene expression and protein levels of the inflammasome will be correlated with 60-day mortality and additional SAILS trial secondary outcomes. We hypothesize that circulating inflammasome levels will serve as a biomarker of severity and mortality of infection-related ALI/ARDS and that inflammasome levels in statin-treated subjects will correlate with clinical outcomes. Specific Aim 2: To determine the cellular localization of expression of the inflammasome complex and role of inflammasome activation on cellular responses and function, using primary neutrophils and monocytes isolated from prospectively enrolled placebo- and statin-treated SAILS subjects (n=100), as well as primary cells isolated from control ICU subjects (n=100). We hypothesize that determining which circulating cells are the predominant source of inflammasome activation will increase sensitivity of the correlation of inflammasome levels with clinical outcomes and that localized activation of the inflammasome will result in mitochondrial dysfunction that will be enhanced in the presence of statin administration.

描述（由申请人提供）：炎症小体最近被描述为一种重要的蛋白质复合物，其中非 NFkB 介导的信号传导途径导致关键促炎细胞因子的上调，包括白细胞介素 (IL)-1b 和 IL- 18.我们小组的成员最近报道，炎症小体在小鼠脓毒症的促炎反应中发挥着关键作用，这种反应依赖于线粒体的完整性和对损伤的完整自噬反应。我们现在提供的数据支持炎症小体在预测人类感染相关的 ALI/ARDS 的严重程度和死亡率方面的重要作用。此外，我们的初步动物研究表明，他汀类药物通过激活炎症小体加剧肺损伤和炎症。因此，我们假设炎症小体的激活在感染相关的 ALI/ARDS 的发展中起着关键作用，并且他汀类药物的施用可能会增加肺损伤期间炎症小体相关的下游细胞因子。特别是，我们与 ARDSnet SAILS 试验研究者（感染相关 ALI/ARDS 中他汀类药物与安慰剂的随机试验）在临床试验 RFA 辅助研究 (HL-12-012) 中的合作提供了一个独特的机会来获得额外的信息。收集关键人类样本来解决这些重要过程。因此，我们建议：具体目标 1：使用安慰剂和他汀类药物治疗的前瞻性血液 (n=100) 和库存血浆样本 (n=600) 确定感染相关 ALI/ARDS 期间炎症小体的基因表达和蛋白质水平航行科目。炎性体的基因表达和蛋白质水平将与 60 天死亡率和其他 SAILS 试验次要结果相关。我们假设循环炎症小体水平将作为感染相关 ALI/ARDS 严重程度和死亡率的生物标志物，并且他汀类药物治疗受试者的炎症小体水平将与临床结果相关。具体目标 2：使用从前瞻性入组安慰剂和他汀类药物治疗的 SAILS 受试者 (n=100) 中分离的原代中性粒细胞和单核细胞，确定炎症小体复合物表达的细胞定位以及炎症小体激活对细胞反应和功能的作用，如以及从对照 ICU 受试者中分离出的原代细胞 (n=100)。我们假设，确定哪些循环细胞是炎症小体激活的主要来源将增加炎症小体水平与临床结果相关性的敏感性，并且炎症小体的局部激活将导致线粒体功能障碍，在给予他汀类药物的情况下会加剧这种功能障碍。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Trends in "usual care" for septic shock.

感染性休克的“常规护理”趋势。

DOI：
发表时间：
2018-09
期刊：
影响因子：
4.5
作者：
Hume, Patrick S;Varon, Jack;Englert, Joshua A;Hurwitz, Shelley;Klompas, Michael;Baron, Rebecca M;Rhee, Chanu
通讯作者：
Rhee, Chanu

Human Sepsis Eicosanoid and Proresolving Lipid Mediator Temporal Profiles: Correlations With Survival and Clinical Outcomes.

人类脓毒症类二十烷酸和促解脂质介质时间特征：与生存和临床结果的相关性。

DOI：
发表时间：
2017-01
期刊：
影响因子：
8.8
作者：
Dalli, Jesmond;Colas, Romain A;Quintana, Carolina;Barragan;Hurwitz, Shelley;Levy, Bruce D;Choi, Augustine M;Serhan, Charles N;Baron, Rebecca M
通讯作者：
Baron, Rebecca M

The authors reply.

作者回复。