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: 9211366
• 负责人: Loren C Denlinger
• 金额: $ 46.89万
• 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 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211366
• 关键词: Activities of Daily Living; Acute; Alveolar Macrophages; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Asthma; Attenuated; Biological Markers; Cell Lineage; Cells; Characteristics; Clinical; Clinical Trials; Coupled; Data; Definity; Development; Dinoprostone; Disease; Eicosanoids; Enzyme Induction; Enzymes; Epithelial; Epithelial Cells; Event; Family; Foundations; Functional disorder; Future; Generations; Goals; Health; Human; Immunoglobulin Class Switching; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Integration Host Factors; Interleukin-1 beta; Knowledge; Lead; Lipids; Lipoxins; Lung; Mediator of activation protein; Mission; Modeling; Nose; Outcome; Pathway interactions; Patients; Pharmacology; Phenotype; Population; Prednisone; Prevention; Prevention strategy; Process; Production; Protocols documentation; Recording of previous events; Recovery; Regulation; 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; asthmatic patient; base; eicosanoid metabolism; experimental study; in vivo; indexing; individual patient; lipid mediator; lipoxin A4; mRNA Expression; monocyte; novel therapeutics; nucleotide receptor; patient oriented; peripheral blood; personalized management; programs; protective effect; public health relevance; receptor; response; tool; transcription factor; Activities of Daily Living; Acute; Alveolar Macrophages; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Asthma; Attenuated; Biological Markers; Cell Lineage; Cells; Characteristics; Clinical; Clinical Trials; Coupled; Data; Definity; Development; Dinoprostone; Disease; Eicosanoids; Enzyme Induction; Enzymes; Epithelial; Epithelial Cells; Event; Family; Foundations; Functional disorder; Future; Generations; Goals; Health; Human; Immunoglobulin Class Switching; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Integration Host Factors; Interleukin-1 beta; Knowledge; Lead; Lipids; Lipoxins; Lung; Mediator of activation protein; Mission; Modeling; Nose; Outcome; Pathway interactions; Patients; Pharmacology; Phenotype; Population; Prednisone; Prevention; Prevention strategy; Process; Production; Protocols documentation; Recording of previous events; Recovery; Regulation; 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; asthmatic patient; base; eicosanoid metabolism; experimental study; in vivo; indexing; individual patient; lipid mediator; lipoxin A4; mRNA Expression; monocyte; novel therapeutics; nucleotide receptor; patient oriented; peripheral blood; personalized management; programs; protective effect; public health relevance; receptor; 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）：尽管最近鉴定出解决炎症的类花生酸介质，但在感染过程中对这些因素的调节尚未得到充分了解。 哮喘恶化通常是由人类鼻病毒感染引起的，但是缺乏时间敏感的，以患者为中心的工具来研究这些事件，这阻碍了急性哮喘治疗的发展。我们的远程目标是更完全了解哮喘加剧的解决方案，以加快康复。 我们已经表明，核苷酸受体P2X7调节COX-2和PGE2产生的表达（后者诱导了促脂蛋白等促脂质）。因此，本提案的总体目标是o定义了调节在HRV体外和体内感染期间eicosanoid-netabolized酶的表达和功能的机制。 作为这一更广泛目标的一部分，中央假设是，PGE2和脂蛋白的跨细胞生成受P2X7诱导的COX-2在肺泡巨噬细胞中的调节，并且这一过程有助于解决HRV触发的促进促进的促进。 我们提出以下特定目标。 SA1）确定HRV感染期间经细胞脂蛋白产生的机制。我们的工作假设是，HRV感染的上皮细胞的启动可以增强P2X7诱导的COX-2表达和PGE2通过肺泡巨噬细胞产生，并且在这些条件下的脂毒素产生需要气道上皮15-LO活性。该目的的主要方法是利用轻度哮喘患者的气道细胞原发性培养物来研究COX-2和15-LO在感染HRV期间的表达和活性的P2X7-DEPNENT机制。 SA2）在HRV诱导的加重过程中确定患者特征和气道样品类固醇因素，这些因素与哮喘症状的快速解决有关。工作假设是，相对于孔功能减弱的患者，P2X7活性正常的哮喘患者将在启动HRV触发的泼尼松爆发后的7天内具有较大比例的受试者，以解决HRV触发的病情，并且急性气道样品中的PGE2水平较高。在这种情况下，主要方法是在严重的哮喘研究计划中使用纵向和加剧方案的背景下，使用新开发的时间敏感工具（哮喘指数）研究加剧。 P2X7的功能能力，在鼻分泌期间的HRV存在或不存在，将评估急性气道样品中PGE2和LXA4水平的水平，以确定其在解决加剧的时间时确定其作为生物标志物的作用。这项贡献是重要的，因为它是一项连续研究的第一步，预计将导致制定药理学策略，该策略将允许患者实体化的管理策略更快地恢复哮喘控制，并代表通过使用经跨性细胞模型来确定体外机制，并依靠体外研究，并代表与现状的新现状，并具有严重的时间表，并依靠时间表的时间。