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性磷脂酶 A2。类二十烷酸合成失调在哮喘的免疫生物学中起着核心作用。新的证据表明，上皮可以通过控制白细胞用来产生促炎类二十烷酸的花生四烯酸（AA）的释放来调节类二十烷酸的产生。磷脂酶 A2 (PLA2) 是一组酶，可催化膜磷脂释放 AA 的限速步骤，从而引发白三烯 (LT) 和前列腺素 (PG) 的产生。最近，已鉴定出 9 种分泌性 PLA2 (sPLA2)，它们与众所周知的 IVa 族胞质 PLA2 (cPLA2a) 协同作用，释放 AA，并优先启动促炎类花生酸的合成，例如半胱氨酰白三烯 (CysLT)。我们的总体假设是，上皮细胞中分泌性 PLA2 的上调可介导哮喘中促炎类二十烷酸的产生增加。类二十烷酸合成失调在哮喘的一种表型中起关键作用，即运动诱发的支气管收缩 (EIB)。具有这种表型的哮喘患者气道中 CysLT 的基础水平升高，并且 CysLT 和其他类二十烷酸（例如 PGD2）的释放在 EIB 期间维持支气管收缩。在初步研究中，我们发现 sPLA2 X 组（sPLA2-X）在患有 EIB 的哮喘患者的诱导痰中相对于正常对照升高，运动挑战后气道中升高，并且在气道上皮中特异性表达。在小鼠哮喘模型中，上皮是sPLA2-X的主要来源，sPLA2-X的遗传缺陷显着抑制气道炎症、支气管高反应性和重塑的发展。在具体目标 1 中，我们将进行基线支气管内活检研究，以确定 EIB 哮喘患者气道上皮中 sPLA2 是否上调。将比较患有 EIB 的哮喘患者、不患有 EIB 的哮喘患者和正常对照之间 AA 释放的关键调节点以及 CysLT 和其他类二十烷酸的合成途径的差异。在具体目标 2 中，我们将对这三组进行运动挑战研究，以确定上皮中 sPLA2 的激活是否会在 EIB 期间启动 CysLT 和其他类二十烷酸的持续释放。将检查上皮内 AA 释放的主要控制点、从释放到气道中的 sPLA2 以及气道内白细胞中的 AA 释放。在具体目标 3 中，我们将使用从各组单独分离的原代支气管上皮细胞并与外周血嗜酸性粒细胞共培养进行体外研究，以检查上皮 sPLA2 对哮喘上皮和上皮细胞释放 AA 的贡献。激活白细胞中的 CysLT 合成。这些研究重点关注特定疾病表型中类二十烷酸产生的免疫生物学，旨在为哮喘新疗法提供重要信息。公共卫生相关性。哮喘是发达国家年轻人中最常见的慢性疾病，成人患病率为 7.2%，儿童患病率为 10.8%。 2002年，哮喘导致48.4万人次住院、190万人次急诊就诊、1390万人次门诊就诊。全国每年因哮喘造成的经济负担超过127亿美元。迫切需要开发新的哮喘疗法，因为哮喘的长期预防性治疗对大约三分之一的哮喘患者无效，而且目前的疗法都不能改变疾病的自然史。这些数据强调需要开发新疗法来提高哮喘治疗的有效性。在本申请中，我们重点关注导致哮喘中促炎类二十烷酸产生增加的机制。初步数据强烈表明分泌性磷脂酶 A2 X 组是促炎类二十烷酸产生的关键调节因子。我们的目标是确定 sPLA2 在哮喘中的功能，以便开发新的疗法并在临床试验中进行测试，从而提高哮喘治疗的有效性并改变哮喘的自然史。