The Role of IL-17 in RSV-induced Mucus and Airway Responsiveness

IL-17 在 RSV 诱导的粘液和气道反应中的作用

• 批准号: 7662456
• 负责人: Ray Stokes Peebles
• 金额: $ 37.29万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662456
• 关键词: Adult; Allergens; Allergic; Asthma; Cell Survival; Cells; Child; Data; Dendritic Cells; Dinoprostone; Goals; Immunobiology; In Vitro; Inflammation; Interleukin-13; Interleukin-17; Interleukins; Lung; Lung Inflammation; Lung diseases; Maintenance; Mediating; Mucous body substance; Mus; Production; Receptor Signaling; Respiratory Syncytial Virus Infections; Respiratory physiology; Respiratory syncytial virus; Role; Signal Transduction; Symptoms; T-Lymphocyte; Virus Diseases; allergic airway inflammation; cytokine; drug development; in vivo; in vivo Model; interleukin-23; mouse model; novel; prevent; receptor

DESCRIPTION (provided by applicant): Viral infections are associated with a majority of asthma exacerbations in both children and adults. In such instances, virally-induced asthma exacerbations most often occur in the setting of underlying pulmonary allergic inflammation. Respiratory syncytial virus (RSV) infections cause a significant number of asthma exacerbations in both children and adults; however, the mechanisms by which RSV infection leads to worsening of asthma symptoms and decreased lung function are not fully defined. Our preliminary data suggests that interleukin (IL)-17A is a critical regulator of RSV-induced airway responsiveness (AR) and mucus expression. In a mouse model, we found that RSV challenge in the setting of allergic lung disease resulted in increased AR and augmented airway mucus expression, compared to mice that were not challenged with RSV during allergic inflammation. The heightened AR and mucus expression in the mice that were RSV-challenged in the presence of allergic inflammation did not correlate with the lung expression of IL-13, a cytokine that is proposed to be central regulator of AR and airway mucus expression, but instead was associated with significantly increased lung IL-17A expression. In contrast, RSV challenge in the absence of allergic lung inflammation did not result in AR, mucus expression, or detectable IL-17A levels. In this proposal, we hypothesize that IL-17A produced by the combination of allergic inflammation and RSV challenge mediates RSV-induced augmented AR and airway mucus. The long-term goals of this proposal are to: 1) fully define the role of IL-17A in the heightened AR and airway mucus expression that results when RSV challenge occurs during ongoing allergic airway inflammation, and 2) define the role of prostaglandin E2 (PGE2) produced by ongoing allergic inflammation in RSV-induced lung IL-23 expression. IL-23 is a cytokine made by dendritic cells which is critical to the expansion and maintenance of IL-17A producing T cells, now known as Th17 cells. Defining the role of IL-17A in the immunobiology of virally-mediated AR and mucus induction may result in novel targets for drug development.

描述（由申请人提供）：病毒感染与儿童和成人的大多数哮喘恶化有关。在这种情况下，病毒诱导的哮喘恶化最常发生在潜在的肺部过敏性炎症的情况下。呼吸综合病毒（RSV）感染在儿童和成人中引起了严重的哮喘患者。但是，RSV感染导致哮喘症状恶化和肺功能降低的机制尚未完全定义。我们的初步数据表明，白介素（IL）-17a是RSV诱导的气道响应能力（AR）和粘液表达的关键调节剂。在小鼠模型中，我们发现在过敏性肺部疾病的情况下，RSV挑战会导致AR增加和增强气道粘液表达，与在过敏性炎症期间没有受到RSV挑战的小鼠相比。在存在过敏性炎症的情况下，在RSV挑战的小鼠中升高的AR和粘液表达与IL-13的肺表达无关，IL-13是一种细胞因子，该细胞因子被认为是AR和气道粘液表达的中心调节剂，而是与肺IL-17A表达显着相关。相反，在没有过敏性肺部炎症的情况下，RSV挑战不会导致AR，粘液表达或可检测的IL-17A水平。在该提案中，我们假设通过过敏性炎症和RSV挑战的组合产生的IL-17A介导了RSV引起的增强AR和气道粘液。该提案的长期目标是：1）完全定义IL-17a在AR和气道粘液表达增强中的作用，这是在RSV挑战在正在进行的过敏性气道炎症过程中发生时会导致的，而2）定义了前列腺素E2（PGE2）（PGE2）的作用，该作用是通过正在进行的过敏性炎症在RSV诱导的LSV诱导的Lung Lung Lung Lung lung lung lung lung lung lung lung lung lung lung lung lung lung l-23中产生的作用。 IL-23是树突状细胞制造的一种细胞因子，对产生IL-17A的T细胞的扩张和维持至关重要，现在称为Th17细胞。定义IL-17a在病毒介导的AR和粘液诱导的免疫生物学中的作用可能导致药物发育的新靶标。