Group V Phospholipase A2 and Pulmonary Inflammation

V 族磷脂酶 A2 与肺部炎症

• 批准号: 6617462
• 负责人: Jonathan Peter Arm
• 金额: $ 33.31万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6617462
• 关键词: anaphylaxis; asthma; eicosanoid metabolism; enzyme mechanism; inflammation; laboratory mouse; leukocyte activation /transformation; leukotrienes; macrophage; mast cell; phospholipase A2; prostaglandins; respiratory hypersensitivity

DESCRIPTION (provided by applicant): Phospholipase A2 (PLA2) hydrolyses the sn-2 position of cell membrane phospholipids to release arachidonic acid, which is metabolized by 5-lipoxygenase to leukotrienes or by prostaglandin endoperoxide synthase (PGHS) to prostaglandins and thromboxane. Leukotrienes (LT) and prostaglandins (PG) have been implicated in diverse physiologic and pathologic processes. Specifically, LTC4 and PGD2, the principal eicosanoid products of the mast cell, have been implicated in bronchial asthma. We have previously described immediate and delayed phases of eicosanoid generation by mouse mast cells. We have demonstrated that cytosolic PLA2 (cPLA2) is essential for the supply of arachidonic acid in each phase. cPLA2 is also required for eicosanoid generation by mouse macrophages. Nevertheless, there is a body of evidence that cPLA2 requires the co-ordinate action of a low molecular weight, secretory PLA2 (sPLA2), most likely group V sPLA2. Group V sPLA2 is expressed by both mast cells and macrophages. In transfection studies, it coupled to cPLA2 in both immediate and delayed phases of eicosanoid generation. There are no specific inhibitors of group V sPLA2. The hypothesis of this proposal is that group V sPLA2 is essential for eicosanoid generation by mast cells and macrophages in vitro, and in the provision of LTC4 and PGD2 in bronchial asthma. To test this hypothesis we have derived mice with disruption of the gene encoding group V sPLA2. In Specific Aim 1 we will use mast cells and macrophages derived from mice with homozygous disruption of group V sPLA2 to determine its role in immediate and delayed phases of eicosanoid generation in response to diverse stimuli. In Specific Aim 2 we will use mice with deletion of group V sPLA2 to determine its role in inflammatory responses of increasing complexity. We will begin with mast cell-dependent passive cutaneous anaphylaxis. We will proceed to active cutaneous and systemic anaphylaxis, in which group V sPLA2 may additionally contribute to the sensitization process. This will lead to mouse models of bronchial asthma in which group V sPLA2 may participate through diverse mechanisms and diverse cellular processes.

描述（由申请人提供）： 磷脂酶A2（PLA 2）水解细胞膜磷脂的sn-2位以释放花生四烯酸，花生四烯酸被5-脂氧合酶代谢为白三烯或被前列腺素内过氧化物合酶（PGHS）代谢为前列腺素和血栓烷。 白三烯（LT）和白藜芦醇苷（PG）参与多种生理和病理过程。具体而言，肥大细胞的主要类花生酸产物LTC 4和PGD 2与支气管哮喘有关。 我们先前已经描述了小鼠肥大细胞产生类花生酸的即时和延迟阶段。 我们已经证明，胞浆PLA 2（cPLA 2）是必不可少的花生四烯酸在每个阶段的供应。 cPLA 2也是小鼠巨噬细胞产生类花生酸所必需的。然而，有大量证据表明cPLA 2需要低分子量分泌型PLA 2（sPLA 2）的协调作用，最可能的是V组sPLA 2。 V组sPLA 2由肥大细胞和巨噬细胞表达。 在转染研究中，它在类花生酸生成的即时和延迟阶段都与cPLA 2偶联。 没有V组sPLA 2的特异性抑制剂。 这一建议的假设是，V组sPLA 2是必需的类花生酸类生成肥大细胞和巨噬细胞在体外，并在提供LTC 4和PGD 2支气管哮喘。 为了验证这一假设，我们已经获得了破坏编码V组sPLA 2的基因的小鼠。 在特定目标1中，我们将使用来自V组sPLA 2纯合破坏的小鼠的肥大细胞和巨噬细胞来确定其在响应于不同刺激的类花生酸生成的即时和延迟阶段中的作用。 在特定目标2中，我们将使用V组sPLA 2缺失的小鼠来确定其在日益复杂的炎症反应中的作用。 我们将开始与肥大细胞依赖性被动皮肤过敏反应。 我们将进行主动皮肤和全身过敏反应，其中V组sPLA 2可能另外有助于致敏过程。 这将导致支气管哮喘的小鼠模型，其中V组sPLA 2可能通过不同的机制和不同的细胞过程参与。