Nucleotide receptor modulation of airway eicosanoids during asthma exacerbations

哮喘急性发作期间气道类二十烷酸的核苷酸受体调节

• 批准号: 8663607
• 负责人: Loren C Denlinger
• 金额: $ 48.02万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-20 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663607
• 关键词: Abbreviations; Activities of Daily Living; Acute; Alveolar; Alveolar Macrophages; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Asthma; Attenuated; Bacteriophages; Biological Markers; Cell Lineage; Cells; Characteristics; Clinical; Clinical Trials; Coupled; Data; Development; Dinoprostone; Disease; Eicosanoids; Enzyme Induction; Enzymes; Epithelial; Epithelial Cells; Event; Family; Foundations; Future; Generations; Goals; Health; Human; Immunoglobulin Class Switching; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Integration Host Factors; Interleukin-1; Knowledge; Lead; Lipids; Lipoxins; Lung; Mediator of activation protein; Mission; Modeling; Nose; Nucleotides; Outcome; Pathway interactions; Patients; Phenotype; Population; Prednisone; Prevention; Prevention strategy; Process; Production; Protocols documentation; Recording of previous events; Recovery; Regulation; Relative (related person); Reporting; Research; Research Infrastructure; Resolution; Rhinovirus; Risk; Role; Sampling; Severities; Stimulus; Symptoms; Testing; Therapeutic; Time; Transcription Factor AP-1; Uncertainty; United States National Institutes of Health; Variant; Whole Blood; Work; airway inflammation; base; eicosanoid metabolism; in vivo; indexing; lipid mediator; lipid metabolism; lipoxin A4; mRNA Expression; macrophage; monocyte; novel therapeutics; nucleotide receptor; patient oriented; peripheral blood; programs; protective effect; public health relevance; receptor; research study; response; tool; transcription factor

DESCRIPTION (provided by applicant): Despite recent identification of eicosanoid mediators that resolve inflammation, the regulation of these factors during infection is not well understood. Asthma exacerbations are commonly triggered by infection with human rhinoviruses, but the lack of time-sensitive, patient-centered tools to study these events hinders development of acute asthma therapies. Our long-range goal is to more completely understand the resolution of asthma exacerbations, in order to hasten recovery. We have shown that the nucleotide receptor P2X7 regulates expression of cox-2 and PGE2 production (the latter of which induces pro-resolution lipids such as lipoxins). As such, the overall objective of the present proposal is o define the mechanisms regulating the expression and function of eicosanoid-metabolizing enzymes during infection by HRV in vitro and in vivo. As part of this broader objective, the central hypothesis is that transcellular generation of PGE2 and lipoxins is regulated by P2X7-induced cox-2 expression in alveolar macrophages, and that this process facilitates resolution of an HRV-triggered exacerbation. We propose the following Specific Aims. SA1) Determine the mechanisms of transcellular lipoxin generation during HRV infection. Our working hypothesis is that priming by HRV-infected epithelial cells enhances P2X7 induced cox-2 expression and PGE2 generation by alveolar macrophages, and that generation of lipoxins under these conditions requires airway epithelial 15-LO activity. The primary approach for this aim is to utilize primary cultures of airway cells from patients with mild asthma to study the P2X7-depndent mechanisms governing the expression and activity of cox-2 and 15-LO during infection with HRV. SA2) Identify the patient characteristics and airway sample eicosanoid factors during HRV- induced exacerbations that are associated with rapid resolution of asthma symptoms. The working hypothesis is that relative to those with attenuated pore function, asthma patients with normal P2X7 activity will have a greater proportion of subjects with a resolving Asthma Index within 7 days of starting a prednisone burst for an HRV-triggered exacerbation and have higher levels of PGE2 in acute airway samples. In this case, the primary approach is to study exacerbations with a newly developed time-sensitive tool, the Asthma Index, in the context of a Longitudinal and Exacerbation Protocols within the Severe Asthma Research Program-3. The functional capacity of P2X7, the presence or absence of HRV in nasal secretions during the exacerbation period and the levels of PGE2 and LXA4 levels in acute airway samples will be assessed to establish their roles as biomarkers in the time to resolving the exacerbation. This contribution is significant because it is the first step in a continuum of research that is expected to lead to development of pharmacologic strategies that will allow for a patient-individualized management strategy to more quickly restore asthma control and represents a new and substantive departure from the status quo by using a transcellular model to identify in vitro mechanisms, coupled with the infrastructure of the Severe Asthma Research Program and the time-sensitive Asthma Index.

描述(由申请人提供)：尽管最近发现了二十烷类介体可以消解炎症，但这些因子在感染过程中的调节还不是很清楚。 哮喘加重通常是由人类鼻病毒感染引发的，但缺乏对时间敏感、以患者为中心的工具来研究这些事件，阻碍了急性哮喘治疗的发展。我们的长期目标是更全面地了解哮喘恶化的解决方案，以加速康复。我们已经证明，核苷酸受体P2X7调节COX-2的表达和PGE2的产生(后者诱导脂蛋白等前分解脂)。因此，本提案的总体目标是确定在体外和体内HRV感染期间二十烷类代谢酶的表达和功能的调节机制。作为这一更广泛目标的一部分，中心假设是PGE2和脂氧素的跨细胞产生受P2X7诱导的肺泡巨噬细胞COX-2表达的调节，这一过程有助于HRV触发的恶化的缓解。我们提出了以下具体目标。SA1)确定HRV感染过程中跨细胞脂素生成的机制。我们的工作假设是，HRV感染的上皮细胞的启动增强了P2X7诱导的COX-2的表达和肺泡巨噬细胞PGE2的产生，而在这些条件下脂氧素的产生需要呼吸道上皮15-LO活性。为达到这一目的，主要的方法是利用轻度哮喘患者的原代培养的呼吸道细胞来研究在HRV感染过程中对P2X7依赖的COX-2和15-LO表达和活性的调控机制。Sa2)确定患者特征和在HRV诱导的加重期间与哮喘症状快速缓解相关的呼吸道样本二十烷类因子。工作假设是，与那些毛孔功能减弱的患者相比，P2X7活性正常的哮喘患者在开始使用强的松冲击治疗HRV引发的恶化的7天内哮喘指数消退的患者比例更高，急性呼吸道样本中的PGE2水平也更高。在这种情况下，主要的方法是使用新开发的时间敏感工具哮喘指数，在重症哮喘研究计划-3的纵向和加重方案的背景下研究加重。将评估P2X7的功能能力、急性加重期鼻分泌物中HRV的存在或不存在以及急性呼吸道样本中PGE2和LXA4的水平，以确定它们作为缓解恶化的时间的生物标志物的作用。这一贡献意义重大，因为它是一系列研究的第一步，预计将导致药物策略的开发，使患者个性化的管理策略能够更快地恢复哮喘控制，并代表着通过使用跨细胞模型来识别体外机制，以及严重哮喘研究计划和时间敏感型哮喘指数的基础设施，与现状的新的实质性偏离。