Group V Phospholipase A2 and Pulmonary Inflammation

V 族磷脂酶 A2 与肺部炎症

• 批准号: 6881152
• 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/6881152
• 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 (PLA2) 水解细胞膜磷脂的 sn-2 位，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素。 白三烯 (LT) 和前列腺素 (PG) 与多种生理和病理过程有关。具体而言，肥大细胞的主要类二十烷酸产物 LTC4 和 PGD2 与支气管哮喘有关。 我们之前已经描述了小鼠肥大细胞产生类二十烷酸的立即阶段和延迟阶段。 我们已经证明，胞质 PLA2 (cPLA2) 对于每个阶段花生四烯酸的供应至关重要。 cPLA2 也是小鼠巨噬细胞生成类二十烷酸所必需的。然而，有大量证据表明 cPLA2 需要低分子量分泌性 PLA2 (sPLA2)（最有可能是 V 族 sPLA2）的协调作用。 V 组 sPLA2 由肥大细胞和巨噬细胞表达。 在转染研究中，它在类二十烷酸生成的立即阶段和延迟阶段与 cPLA2 偶联。 V 组 sPLA2 没有特异性抑制剂。 该提议的假设是 V 族 sPLA2 对于体外肥大细胞和巨噬细胞生成类二十烷酸以及在支气管哮喘中提供 LTC4 和 PGD2 至关重要。 为了验证这一假设，我们衍生了编码 V 组 sPLA2 的基因被破坏的小鼠。 在具体目标 1 中，我们将使用源自 V 组 sPLA2 纯合破坏的小鼠的肥大细胞和巨噬细胞来确定其在响应不同刺激的类二十烷酸生成的立即和延迟阶段中的作用。 在特定目标 2 中，我们将使用删除 V 组 sPLA2 的小鼠来确定其在日益复杂的炎症反应中的作用。 我们将从肥大细胞依赖性被动皮肤过敏反应开始。 我们将继续讨论活性皮肤和全身过敏反应，其中 V 组 sPLA2 可能另外有助于致敏过程。 这将产生支气管哮喘的小鼠模型，其中 V 族 sPLA2 可能通过不同的机制和不同的细胞过程参与其中。