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

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）：尽管最近鉴定了类二十烷酸介质可以解决炎症，但这些因素在感染过程中的调节尚不清楚。 哮喘加重通常是由人类鼻病毒感染引发的，但缺乏时间敏感、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急性发作的解决方法，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（后者诱导促分解脂质，例如脂氧素）。因此，本提案的总体目标是确定在体外和体内 HRV 感染期间调节类二十烷酸代谢酶的表达和功能的机制。 作为这一更广泛目标的一部分，中心假设是 PGE2 和脂氧素的跨细胞生成受到肺泡巨噬细胞中 P2X7 诱导的 cox-2 表达的调节，并且该过程有助于解决 HRV 触发的恶化。 我们提出以下具体目标。 SA1)确定HRV感染期间跨细胞脂氧素产生的机制。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 表达和肺泡巨噬细胞的 PGE2 生成，并且在这些条件下脂氧素的生成需要气道上皮 15-LO 活性。实现这一目标的主要方法是利用轻度哮喘患者气道细胞的原代培养物来研究 HRV 感染期间控制 cox-2 和 15-LO 表达和活性的 P2X7 依赖性机制。 SA2) 确定 HRV 诱发的恶化期间的患者特征和气道样本类二十烷酸因子，这些因子与哮喘症状的快速缓解相关。工作假设是，相对于毛孔功能减弱的患者，P2X7 活性正常的哮喘患者在开始泼尼松爆发治疗 HRV 触发的病情加重后 7 天内，哮喘指数缓解的比例更高，并且急性气道样本中 PGE2 水平更高。在这种情况下，主要方法是在严重哮喘研究计划 3 内的纵向和急性加重方案的背景下，使用新开发的时间敏感工具哮喘指数来研究急性加重。 将评估 P2X7 的功能能力、恶化期间鼻分泌物中是否存在 HRV 以及急性气道样本中的 PGE2 和 LXA4 水平，以确定它们在解决恶化时作为生物标志物的作用。这一贡献意义重大，因为它是连续研究的第一步，预计将导致药理学策略的发展，使患者个体化的管理策略能够更快地恢复哮喘控制，并通过使用跨细胞模型来识别体外机制，结合严重哮喘研究计划的基础设施和时间敏感的哮喘指数，代表了对现状的新的实质性偏离。

项目成果

Oxidized-ATP Attenuates Kidney Allograft Rejection By Inhibiting T-Cell, B-Cell, and Macrophage Activity.

氧化-ATP 通过抑制 T 细胞、B 细胞和巨噬细胞活性来减轻肾同种异体移植排斥。

• DOI: 10.34067/kid.0000692019
• 发表时间: 2020
• 期刊: Kidney360
• 作者: Ding,Xiang;Wilson,NancyA;Redfield3rd,RobertR;Panzer,SarahE;Verhoven,Bret;Reese,ShannonR;Zhong,Weixiong;Shi,Lei;Burlingham,WilliamJ;Denlinger,LorenC;Djamali,Arjang
• 通讯作者: Djamali,Arjang