Secretory Phospholipase A2s in Airway Pathophysiology

分泌性磷脂酶 A2 在气道病理生理学中的作用

• 批准号: 7459390
• 负责人: TEAL S HALLSTRAND
• 金额: $ 39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459390
• 关键词: Accident and Emergency department; Adult; Air; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Asthma; Biopsy; Bronchoconstriction; Cells; Child; Chronic Disease; Clinical Trials; Coculture Techniques; Data; Development; Dinoprostone; Disease; Economic Burden; Effectiveness; Eicosanoid Production; Eicosanoids; Enzymes; Epithelial; Epithelial Cells; Epithelium; Exercise; Functional disorder; Generations; Genetic; Goals; Hospitalization; Hydroxyeicosatetraenoic Acids; Immunobiology; In Vitro; Inflammatory; Leukocytes; Leukotriene Production; Leukotrienes; Mediating; Membrane; Modeling; Mus; Natural History; Numbers; Outpatients; Pathway interactions; Patients; Phenotype; Phospholipase; Phospholipase A2; Phospholipids; Play; Prevalence; Principal Investigator; Process; Production; Prostaglandin D2; Prostaglandins; Public Health; Rate; Relative (related person); Role; Source; Sputum; Testing; Treatment Effectiveness; Up-Regulation; Visit; airway epithelium; airway inflammation; asthmatic airway; base; controlled release; cysteinyl-leukotriene; design; disease natural history; disease phenotype; eosinophil; group X secretory phospholipase A(2); improved; interest; leukotriene-C4 synthase; lipoxin A4; novel; peripheral blood; programs; response; surfactant; young adult

DESCRIPTION (provided by applicant): Secretory Phospholipase A2s in Airway Pathophysiology. Dysregulated eicosanoid synthesis plays a central role in the immunobiology of asthma. Emerging evidence indicates that the epithelium can regulate eicosanoid production by controlling the release of arachidonic acid (AA) used by leukocytes to generate pro-inflammatory eicosanoids. The phospholipase A2s (PLA2)s are a group of enzymes that catalyze the rate-limiting step of AA release from membrane phospholipids initiating the production of leukotrienes (LT)s and prostaglandins (PG)s. Recently, 9 secretory PLA2s (sPLA2)s have been identified that act in concert with the well-described group IVa cytosolic PLA2 (cPLA2a) to release AA and preferentially initiate synthesis of pro-inflammatory eicosanoids such as cysteinyl leukotrienes (CysLT)s. Our overall hypothesis is that upregulation of secretory PLA2s in the epithelium mediates increased production of pro-inflammatory eicosanoids in asthma. A phenotype of asthma where dysregulated eicosanoid synthesis plays a critical role is in exercise-induced bronchoconstriction (EIB). Asthmatics with this phenotype have increased basal levels of CysLTs in their airways, and the release of CysLTs and other eicosanoids such as PGD2 sustain bronchoconstriction during EIB. In preliminary studies, we found that sPLA2 group X (sPLA2-X) is elevated in induced sputum of asthmatics with EIB relative to normal controls, increases in the airways following exercise challenge, and is specifically expressed in airway epithelium. In the murine model of asthma, the epithelium is a major source of sPLA2-X, and genetic deficiency of sPLA2-X markedly inhibits the development airway inflammation, bronchial hyperresponsiveness and remodeling. In Specific Aim 1, we will conduct a baseline endobronchial biopsy study to determine if asthmatics with EIB have upregulation of sPLA2s in the airway epithelium. Differences in the key regulatory points for AA release, and the synthetic pathways for CysLTs and other eicosanoids will be compared between asthmatics with EIB, asthmatics without EIB, and normal controls. In Specific Aim 2 we will conduct an exercise challenge study in these three groups to determine if activation of sPLA2s in the epithelium initiates the sustained release of CysLTs and other eicosanoids during EIB. The major control points for AA release within the epithelium, from sPLA2s released into the airways, and in leukocytes residing within the airways will be examined. In Specific Aim 3, we will conduct in vitro studies with primary bronchial epithelial cells isolated from each of the groups alone and co-cultured with peripheral blood eosinophils to examine the contribution of epithelial sPLA2s to the release of AA from the asthmatic epithelium and the epithelial activation of CysLT synthesis in leukocytes. These studies focusing on the immunobiology of eicosanoid production in a specific disease phenotype are designed to provide important information leading to new therapies for asthma. PUBLIC HEALTH RELEVANCE. Asthma is the most prevalent chronic disease of young adults in the developed world with a prevalence of 7.2% in adults, and 10.8% in children. Asthma led to 484,000 hospitalizations, 1.9 million emergency department visits, and 13.9 million outpatient visits in 2002. The national annual economic burden of asthma is over 12.7 billion dollars. There is a pressing need to develop new therapies for asthma because long-term preventative treatments for asthma are ineffective in about a third of patients with asthma, and none of the current therapies alter the natural history of the disease. These data highlight the need to develop new therapies that will improve the effectiveness of treatments for asthma. In this application we focus on the mechanism leading to increased production of pro-inflammatory eicosanoid in asthma. Preliminary data strongly implicate secretory phospholipase A2 group X as a key regulator of pro-inflammatory eicosanoid production. Our goal is to determine the function of the sPLA2s in asthma so that novel therapies can be developed and tested in clinical trials that will improve the effectiveness of asthma treatments and alter the natural history of asthma.

描述（由申请人提供）：气道病理生理学中的分泌磷脂酶A2。不能调节的类花生酸合成在哮喘的免疫生物学中起着核心作用。新兴的证据表明，上皮可以通过控制白细胞用来产生促炎性类花生酸酯的蛛网膜化酸（AA）来调节类固醇的产生。磷脂酶A2S（PLA2）S是一组酶，可催化从膜磷脂释放的速率限制步骤，从而启动白细胞生产（LT）S和前列腺素（PG）S的产生。最近，已经确定了9个分泌PLA2S（SPLA2）S与描述良好的组IVA胞质PLA2（CPLA2A）一起起作用，以释放AA，并优先启动促炎性类生物烷（例如墨西哥cysteinylylemanets）的合成。我们的总体假设是，上皮中分泌PLA2的上调介导哮喘中促炎性类花生酸的产生增加。哮喘的表型，其中失调的类花生酸合成起着至关重要的作用，这在运动诱导的支气管收缩（EIB）中。具有这种表型的哮喘患者在其呼吸道中的基础水平增加，并且在EIB期间释放了Cyslt和其他类花生酸酯（例如PGD2）维持支气管收缩。在初步研究中，我们发现SPLA2组X（SPLA2-X）在诱导的具有EIB相对于正常对照的哮喘患者的痰液中升高，运动攻击后的气道增加，并且在气道上皮中特别表达。在哮喘的鼠模型中，上皮是SPLA2-X的主要来源，SPLA2-X的遗传缺乏显着抑制了发育气道炎症，支气管性高反应性和重塑。在特定的目标1中，我们将进行基线支撑型活检研究，以确定带有EIB的哮喘患者是否在气道上皮中上调SPLA2。 AA释放的关键调节点的差异以及Cyslts和其他类固醇的合成途径的差异将在具有EIB的哮喘患者，没有EIB的哮喘患者和正常对照组之间进行比较。在特定的目标2中，我们将在这三组中进行一项运动挑战研究，以确定上皮中SplA2s的激活是否会启动EIB期间Cyslts和其他类固醇的持续释放。上皮释放的主要控制点，从释放到气道中的SPLA2以及居住在气道中的白细胞中。在特定的目标3中，我们将对单独从每个组分离的原发支气管上皮细胞进行体外研究，并与外周血血嗜酸性粒细胞共同培养，以研究上皮Spla2s对从哮喘上皮的AA释放AA的贡献，以及Cyslt Cynatheses in leukcycytess in leukcycytessessessessessessessessessessessessessessessessessessessessessessessesses。这些研究重点介绍了特定疾病表型中类花生酸的免疫生物学，旨在提供重要的信息，从而为哮喘提供新的疗法。公共卫生相关性。哮喘是发达国家中最普遍的年轻人慢性疾病，成年人患病率为7.2％，儿童为10.8％。 2002年，哮喘导致484,000次住院，190万急诊室就诊和1390万个门诊就诊。哮喘的全国年度经济负担超过127亿美元。迫切需要开发哮喘的新疗法，因为长期预防哮喘的预防性治疗在大约三分之一的哮喘患者中无效，而且目前的疗法均未改变这种疾病的自然史。这些数据强调了开发新疗法的必要性，以提高哮喘治疗疗法的有效性。在此应用中，我们着重于导致哮喘促炎性类花生酸酯产生增加的机制。初步数据强烈暗示分泌的磷脂酶A2组X是促炎类花生酸的关键调节剂。我们的目标是确定SPLA2在哮喘中的功能，以便可以在临床试验中开发和测试新的疗法，以提高哮喘治疗的有效性并改变哮喘的自然史。