The Inflammasome: A Novel Biomarker in ALI/ARDS

炎症小体：ALI/ARDS 的新型生物标志物

• 批准号: 8661275
• 负责人: Rebecca M Baron
• 金额: $ 43.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661275
• 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-1; 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; TNF gene; Toll-like receptors; 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

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）：炎性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的促炎细胞因子的上调，包括白介素（IL）-1B和IL-18。我们小组的成员最近报道说，炎性体在鼠败血症的炎性反应中起着至关重要的作用，这种反应取决于线粒体完整性和对损伤的完整自噬反应。现在，我们提出了支持炎症体在预测与人类感染相关的ALI/ARDS期间的严重程度和死亡率方面的重要作用的数据。此外，我们的初步动物研究表明，他汀类药物通过激活炎症加剧了肺损伤和炎症。因此，我们假设炎性体的激活在与感染相关的ALI/ARDS的发展中起着至关重要的作用，而他汀类药物的给药可能会增加肺部损伤期间与炎症体相关的下游细胞因子。特别是，我们与Ardsnet Sails试验研究者（在与感染相关的ALI/ARDS中的他汀类药物与安慰剂的随机试验）中的合作中进行了临床试验RFA（HL-12-012）的辅助研究）提供了一个独特的机会，可为获得其他关键人类样本的收集，以解决这些重要过程。因此，我们提出：特定目的1：使用前瞻性收集的血液（n = 100）和安慰剂和他汀类药物治疗的帆受试者确定与感染相关的ALI/ARDS炎症体的基因表达和蛋白质水平。炎性体的基因表达和蛋白质水平将与60天的死亡率和其他帆试验次要结局相关。我们假设循环炎性体水平将成为与感染相关的ALI/ARDS的严重程度和死亡率的生物标志物，并且他汀类药物治疗的受试者中的炎性体水平将与临床结果相关。具体目的2：确定炎性体复合物表达的细胞定位以及炎症体激活在细胞反应和功能上的作用，使用原代嗜中性粒细胞和单核细胞与前瞻性纳入的安慰剂和他汀类药物治疗的帆受试者（n = 100）（n = 100）分离出来，以及与对照ICU受试者分离的主细胞（n = 100）（n = 100）。我们假设确定哪些循环细胞是炎性体激活的主要来源，将提高炎性体水平与临床结局的相关性的敏感性，并且炎性体的局部激活将导致线粒体功能障碍，这将在催产剂施用的情况下会增强。