Group V Phospholipase A2 and Pulmonary Inflammation

V 族磷脂酶 A2 与肺部炎症

• 批准号: 8255636
• 负责人: HOWARD R KATZ
• 金额: $ 36.75万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255636
• 关键词: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acute; Agonist; Alveolar Macrophages; Anabolism; Antigens; Arachidonic Acids; Attenuated; Biological Process; Blood Vessels; Bone Marrow; Breeding; Calcium; Candida albicans; Cell Wall; Cell membrane; Cells; Data; Defect; Dinoprostone; Eicosanoids; Endosomes; Enzymes; Event; Extracellular Signal Regulated Kinases; Family; Fatty Acids; Funding; Gene Deletion; Gene Expression; Generations; Genetic Transcription; Glycerophospholipids; Goals; Golgi Apparatus; Greater sac of peritoneum; Host Defense; Hydrolysis; IgE; Immune response; Inbred BALB C Mice; Infection; Infection Control; Infectious Agent; Inflammatory Response; Ingestion; Injection of therapeutic agent; Invaded; JUN gene; Knockout Mice; Leukotriene C4; Leukotriene E4; Leukotrienes; Ligands; Lipids; Location; Lung; Lysophospholipids; Macrophage Activation; Mitogen-Activated Protein Kinases; Modeling; Mouse Strains; Mus; Natural Immunity; Nonesterified Fatty Acids; Organism; Peritoneal Macrophages; Phagocytosis; Phagosomes; Phase; Phospholipase A2; Phosphorylation; Phosphotransferases; Pneumonia; Positioning Attribute; Prostaglandin D2; Prostaglandins; Receptor Signaling; Recycling; Regulation; Role; Signal Transduction; Signaling Molecule; Site; Stem Cell Factor; Stimulus; TLR2 gene; Toll-Like Receptor 2; Toll-like receptors; Yeasts; Zymosan; cyclooxygenase 2; enzyme structure; fungus; group V phospholipase A2; group V secretory phospholipase A2; innate immune function; insight; killings; macrophage; mast cell; microorganism; mutant; novel; pathogen; response; sensor

DESCRIPTION (provided by applicant): The broad goal of this application is to understand the biological function(s) of an enzyme termed secretory group V phospholipase A2 (sPLA2), particularly as it pertains to control of infections and pulmonary inflammation. Group V sPLA2 is prominently expressed in mast cells and macrophages, cells that are critical for sensing harmful organisms at their sites of entry into the body and in generating the acute inflammatory response that is essential for efficient clearing and killing of these pulmonary pathogens. Group V sPLA2 regulates the generation of leukotrienes and prostaglandins in both mast cells and macrophages in response to stimuli that are surrogates for invading pathogens, namely zymosan, derived from yeast cell walls, and agonists of toll-like receptor (TLR)-2. Our early studies indicate that the enzyme regulates phagocytosis and killing of the yeast Candida albicans in pulmonary macrophages and activation of signaling molecules called mitogen-activated protein kinases in response to TLR2 stimulation of mast cells. The aims of this proposal are therefore to understand how group V sPLA2 regulates phagocytosis and killing of fungi; to understand how group V sPLA2 regulates TLR signaling in mast cells; and to determine the importance of the enzyme for generation of pulmonary inflammatory responses to invading microorganisms and their clearance from the host. To achieve these aims we will compare the generation of lipids and early signaling events following zymosan stimulation between macrophages that lack group V sPLA2 and normal macrophages. We will express normal and mutant forms of group V sPLA2 in macrophages to examine the relationship between the structure of the enzyme and its function. We will compare the generation of lipids and early signaling events in response to TLR2 stimulation between mast cells that lack group V sPLA2 and normal mast cells. We will study the subcellular location of group V sPLA2 in mast cells stimulated through TLR2. Finally, we will use mice that lack group V sPLA2 to study the relevance of these findings in models of fungal pulmonary infection. The lung is a major site of entry into the body for infectious organisms. The ability to mount an effective and appropriate inflammatory response to these organisms is essential for survival. The proposed studies will define the function of group V phospholipase A2 in host defense. They will provide new information on the function of this enzyme, which is presently poorly understood. These studies will provide new insight into the regulation of pulmonary inflammation and innate immunity.

描述（由申请人提供）：本申请的广泛目标是理解称为分泌型V族磷脂酶A2（sPLA 2）的酶的生物学功能，特别是当其涉及控制感染和肺部炎症时。V组sPLA 2在肥大细胞和巨噬细胞中显着表达，这些细胞对于在有害生物进入体内的部位感知有害生物以及产生急性炎症反应至关重要，而急性炎症反应对于有效清除和杀死这些肺部病原体至关重要。V组sPLA 2调节肥大细胞和巨噬细胞中响应于作为入侵病原体的替代物的刺激物（即来源于酵母细胞壁的酵母聚糖和Toll样受体（TLR）-2的激动剂）的白三烯和白细胞介素的产生。我们的早期研究表明，该酶调节吞噬作用和杀死肺巨噬细胞中的酵母菌白色念珠菌，并激活称为丝裂原活化蛋白激酶的信号分子，以响应肥大细胞的TLR 2刺激。因此，本提案的目的是了解V组sPLA 2如何调节吞噬作用和杀死真菌;了解V组sPLA 2如何调节肥大细胞中的TLR信号传导;并确定酶对入侵微生物的肺部炎症反应的产生及其从宿主中清除的重要性。为了实现这些目标，我们将比较缺乏V组sPLA 2的巨噬细胞和正常巨噬细胞之间的酵母多糖刺激后脂质和早期信号事件的产生。我们将在巨噬细胞中表达V组sPLA 2的正常和突变形式，以检查酶的结构与其功能之间的关系。我们将比较缺乏V组sPLA 2的肥大细胞和正常肥大细胞对TLR 2刺激的脂质生成和早期信号事件。我们将研究V组sPLA 2在通过TLR 2刺激的肥大细胞中的亚细胞定位。最后，我们将使用缺乏V组sPLA 2的小鼠来研究这些发现在真菌肺部感染模型中的相关性。肺是感染性微生物进入体内的主要部位。对这些生物体产生有效和适当的炎症反应的能力对生存至关重要。这些研究将明确V族磷脂酶A2在宿主防御中的功能。他们将提供关于这种酶的功能的新信息，这是目前知之甚少的。这些研究将为肺部炎症和先天免疫的调节提供新的见解。

项目成果

A novel anti-inflammatory role for secretory phospholipase A2 in immune complex-mediated arthritis.

• DOI: 10.1002/emmm.201000072
• 发表时间: 2010-05
• 期刊: EMBO MOLECULAR MEDICINE
• 影响因子: 11.1
• 作者: Boilard, Eric;Lai, Ying;Larabee, Katherine;Balestrieri, Barbara;Ghomashchi, Farideh;Fujioka, Daisuke;Gobezie, Reuben;Coblyn, Jonathan S.;Weinblatt, Michael E.;Massarotti, Elena M.;Thornhill, Thomas S.;Divangahi, Maziar;Remold, Heinz;Lambeau, Gerard;Gelb, Michael H.;Arm, Jonathan P.;Lee, David M.
• 通讯作者: Lee, David M.