Arachidonic Acid Mediated Regulation of Secretory IgA Levels in the Airways

花生四烯酸介导的气道分泌型 IgA 水平调节

• 批准号: 7706939
• 负责人: DOUGLAS A KUPERMAN
• 金额: $ 22.88万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-13 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706939
• 关键词: Amino Acids; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Arginine; Bacteria; Binding; Biochemical; Breeding; Data; Dendritic Cells; Development; Disease; Enzymes; Epithelial Cells; Exposure to; FDA approved; Generations; Genetic; Goals; Health; Immunoglobulin A; Infection; Lead; Life; Link; Lipoxygenase; Lipoxygenase Inhibitors; Lung; Mediating; Mediator of activation protein; Medicine; Metabolism; Modeling; Molecular; Monitor; Mucosal Immunity; Mus; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Pathway; Oligosaccharides; Pathway interactions; Patients; Performance; Polymeric Immunoglobulin Receptors; Predisposition; Production; Protein Isoforms; Regulation; Reporting; Research; Secretory Immunoglobulin A; Side; Signal Transduction; Site; Surface; System; Testing; Therapeutic; United States National Institutes of Health; Wild Type Mouse; Work; Zileuton; arginase; combat; cysteinyl-leukotriene; human NOS2A protein; improved; inhibitor/antagonist; montelukast; mucosal vaccine; novel; pathogen; prevent; receptor; response

DESCRIPTION (provided by applicant): Secretory IgA (SIgA) is an important mediator of mucosal immunity. Strategies that boost SIgA production in the airways will confer benefit to patients that have become susceptible to infections caused by airborne pathogens. Our studies point to a novel molecular pathway by which arachidonic acid metabolism regulates the basal rate of SIgA production in the airways. As such our studies might support the development of a medicine that can be used as a co-therapy with mucosal vaccines to permanently boost the levels of SIgA in the airways; thus providing a very long-lived pathogen-specific protection. However, because of the polyreactivity of innate SIgA and the ability of its oligosaccharide side-chains to bind directly to bacteria, our studies might also support the development of a stand-alone therapy to boost the generally protective mucosal immunity that is afforded by SIgA. Our preliminary studies support a working model in which the magnitude of SIgA production in the airways is largely dependent upon the levels of constitutive generation of 12/15- lipoxygenase (LO) and 5-LO metabolites produced by airway epithelial cells and their downstream ability to induce nitric oxide (NO) production by dendritic cells. We will test this hypothesis by completing two specific aims. Specific Aim 1. To determine if cysteinyl leukotrienes (CysLTs) mediate baseline NO and SIgA production in the airways of wild-type mice and if increased CysLTs mediate the increase of NO and SIgA observed in the airways of 12/15-LO-/- mice. Specific Aim 2. To determine if NO mediates baseline SIgA production in the airways of wild-type mice and if increased NO mediates the increase of SIgA production observed in the airways of 12/15-LO-/- mice. We estimate that our proposed studies will be complete in approximately two-years and we anticipate that they will lead to additional questions regarding the basic mechanisms by which SIgA is regulated in the airways. Our proposed mouse studies will utilize very well characterized genetic and pharmacologic approaches. Medicines that target the LO and NO pathways are already developed or emerging. Thus, we believe that our proposed studies will reveal a novel mechanistic pathway that can be readily manipulated to dramatically boost SIgA levels in the airways. Our studies indicate that the arachidonic acid metabolizing enzymes, 12/15-lipoxygenase and 5-lipoxygenase regulate the first-line defense molecule secretory IgA in the conducting airways. We hypothesize that this is due to their ability to produce cysteinyl leukotrienes and the effects of the cysteinyl leukotrienes are mediated by nitric oxide. Manipulation of this pathway would be predicted to result in induction of secretory IgA and decreased susceptibility to pulmonary infections. Our studies will provide valuable information supporting the goal of the National Institutes of Health to prevent disease and promote health.

描述（由申请人提供）：分泌型伊加（SIgA）是粘膜免疫的重要介质。增加气道中SIgA产生的策略将为易受空气传播病原体感染的患者带来好处。我们的研究指出了一种新的分子途径，花生四烯酸代谢调节气道中SIgA产生的基础速率。因此，我们的研究可能支持开发一种药物，该药物可用作粘膜疫苗的联合治疗，以永久提高气道中SIgA的水平;从而提供非常长寿命的病原体特异性保护。然而，由于先天性SIgA的多反应性及其寡糖侧链直接与细菌结合的能力，我们的研究也可能支持开发一种独立的治疗方法，以增强SIgA提供的一般保护性粘膜免疫。我们的初步研究支持一个工作模型，其中SIgA在气道中的生产量在很大程度上取决于气道上皮细胞产生的12/15-脂氧合酶（LO）和5-LO代谢产物的组成型生成水平及其下游诱导树突状细胞产生一氧化氮（NO）的能力。我们将通过完成两个具体目标来检验这一假设。具体目标1.确定半胱氨酰白三烯（CysLT）是否介导野生型小鼠气道中的基线NO和SIgA产生，以及CysLT增加是否介导12/15-LO-/-小鼠气道中观察到的NO和SIgA增加。具体目标2。确定NO是否介导野生型小鼠气道中的基线SIgA产生，以及增加的NO是否介导在12/15-LO-/-小鼠气道中观察到的SIgA产生的增加。我们估计，我们提出的研究将在大约两年内完成，我们预计，他们将导致更多的问题，其中SIgA的基本机制，在气道调节。我们提出的小鼠研究将利用非常充分表征的遗传学和药理学方法。靶向LO和NO途径的药物已经开发或正在出现。因此，我们相信我们提出的研究将揭示一种新的机制途径，可以很容易地操纵，以显着提高气道中的SIgA水平。我们的研究表明，花生四烯酸代谢酶，12/15-脂氧合酶和5-脂氧合酶调节的第一线防御分子分泌IgA的传导气道。我们假设这是由于它们能够产生半胱氨酰白三烯，并且半胱氨酰白三烯的作用是由一氧化氮介导的。该途径的操作将被预测导致分泌型伊加的诱导和对肺部感染的易感性降低。我们的研究将提供有价值的信息，支持美国国立卫生研究院预防疾病和促进健康的目标。