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

基本信息

批准号：
8699815
负责人：
TEAL S HALLSTRAND
金额：
$ 40.6万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8699815
关键词：
Active Sites Address Adoptive Transfer Allergens Allergic inflammation Asthma Bone Marrow Breathing Bronchoconstriction C-Type Lectins Cavia Cells Chimera organism Data Dependence Development Eicosanoid Production Eicosanoids Enzymes Epithelial Epithelial Cells Epithelium Figs - dietary Functional disorder Funding Generations Genes Human Hyperpnea Immune response Inflammation Knock-out Lead Leukotrienes Liquid substance Mediating Modeling Mucous body substance Mus Myelogenous Ovalbumin Patients Phase Phenotype Phospholipase Phospholipase A2 Play Predisposition Prostaglandins Proteins Pyroglyphidae Regulation Relative (related person)Research Role Source Testing Work airway epithelium airway hyperresponsiveness airway inflammation base eosinophil immunopathology in vivo inhibitor/antagonist insight macrophage mast cell monocyte novel novel strategies novel therapeutic intervention prevent public health relevance translational study

项目摘要

DESCRIPTION (provided by applicant): The phospholipase A2s (PLA2)s are a group of enzymes that catalyze the rate-limiting step in the formation of eicosanoids such as leukotrienes (LT)s and prostaglandins (PG)s. This application for sustained support focuses on secreted phospholipase A2 group X (sPLA2-X) in the pathophysiology of asthma. During the prior funding cycle, we addressed the novel hypothesis that the airway epithelium serves as a regulator of eicosanoid production through the expression of sPLA2s. A total of 10 mammalian sPLA2s have been described. From our research, sPLA2-X emerged as the dominant sPLA2 expressed in the airways. The amount of sPLA2-X protein is increased in the airway lining fluid of patients with asthma, and is strongly expressed in the airway epithelium. Further, we found that sPLA2-X initiates LT synthesis in target cells including eosinophils and mast cells implicated in asthma. Murine models indicate that sPLA2-X is necessary for the development of ovalbumin-induced airway inflammation and airway hyperresponsiveness (AHR). We provide new data that sPLA2-X is necessary for the development of house dust mite induced airway inflammation as well as macrophage polarization. In this application we strive to further elucidate the mechanism by which sPLA2-X initiates airway inflammation and mediates bronchoconstriction in asthma. Our primary hypothesis is that epithelial-derived sPLA2-X is necessary for the development of allergen- induced airway inflammation and serves as an initiator of bronchoconstriction in inflamed airways. A corollary hypothesis is that sPLA2-X plays a crucial role in the adaptive immune response to inhaled allergen through macrophage polarization. In Specific Aim 1 we focus on the specific role of epithelial- derived sPLA2-X during the development of allergen-induced airway immunopathology, and examine the function of epithelial sPLA2-X during the sensitization versus effector phases. Using primary human epithelial cells, we examine the regulation of secretion and activation of sPLA2-X. In Specific Aim 2, we examine the role of sPLA2-X in macrophage polarization towards a M2 phenotype, and the precise role of the sPLA2-X macrophage axis in the adaptive immune response to allergen. In Specific Aim 3, we conduct a translational study on the role of sPLA2-X during hyperpnea-induced bronchoconstriction using a novel pharmacological inhibitor of sPLA2-X in a guinea pig model. These studies will provide important insights into the mechanism of allergen-induced airway dysfunction mediated by the epithelium and a strong basis for the further development of a new approach to treating asthma through the selective inhibition of sPLA2-X.

描述（由申请人提供）：磷脂酶A2（PLA2）是一组催化类二十烷酸（例如白三烯（LT）和前列腺素（PG））形成中的限速步骤的酶。此持续支持应用重点关注哮喘病理生理学中的分泌型磷脂酶 A2 X 组 (sPLA2-X)。在之前的资助周期中，我们提出了一个新的假设，即气道上皮通过 sPLA2 的表达来调节类花生酸的产生。总共描述了 10 种哺乳动物 sPLA2。根据我们的研究，sPLA2-X 成为气道中表达的主要 sPLA2。哮喘患者气道内壁液中sPLA2-X蛋白的量增加，并且在气道上皮中强烈表达。此外，我们发现 sPLA2-X 启动靶细胞中的 LT 合成，包括与哮喘有关的嗜酸性粒细胞和肥大细胞。小鼠模型表明 sPLA2-X 对于卵清蛋白诱导的气道炎症和气道高反应性 (AHR) 的发展是必需的。我们提供的新数据表明 sPLA2-X 对于屋尘螨诱导的气道炎症以及巨噬细胞极化的发展是必需的。在此应用中，我们努力进一步阐明 sPLA2-X 引发气道炎症并介导哮喘支气管收缩的机制。我们的主要假设是，上皮来源的 sPLA2-X 对于过敏原诱导的气道炎症的发展是必需的，并且是发炎气道中支气管收缩的引发剂。一个推论假设是 sPLA2-X 通过巨噬细胞极化在对吸入过敏原的适应性免疫反应中发挥着至关重要的作用。在具体目标 1 中，我们重点关注上皮来源的 sPLA2-X 在过敏原诱导的气道免疫病理学发展过程中的具体作用，并检查上皮 sPLA2-X 在致敏阶段与效应阶段的功能。使用原代人上皮细胞，我们检查了 sPLA2-X 的分泌和激活的调节。在具体目标 2 中，我们研究了 sPLA2-X 在巨噬细胞极化为 M2 表型中的作用，以及 sPLA2-X 巨噬细胞轴在对过敏原的适应性免疫反应中的精确作用。在具体目标 3 中，我们在豚鼠模型中使用 sPLA2-X 的新型药理学抑制剂，对 sPLA2-X 在呼吸过度引起的支气管收缩过程中的作用进行了转化研究。这些研究将为了解上皮介导的过敏原诱导的气道功能障碍的机制提供重要的见解，并为进一步开发通过选择性抑制 sPLA2-X 治疗哮喘的新方法奠定坚实的基础。