PGI2 inhibition of pulmonary innate allergic immune responses

过敏性气道炎症是哮喘的标志，哮喘是美国最常见的慢性疾病之一。 States.第2组先天淋巴样细胞（ILC 2）是最近描述的细胞类型，是一种更有效的生产者 IL-5和IL-13在每个细胞的基础上比CD 4 + Th 2细胞高，并且越来越多的证据表明ILC 2是关键的 过敏性炎症反应的发生和扩大。在此VA Merit的最后一个资助周期中， 奖，我们报告说，前列腺素（PG）I2负调节ILC 2功能，在体外和体内， 抑制先天免疫介导的气道嗜酸性粒细胞增多、粘液化生和气道反应性， 哮喘表型的主要特征。我们新的体内初步数据强烈表明，PGI 2 信号传导抑制Alt Ex诱导的IL-33的气道释放，IL-33是一种结合到 ILC 2和其他细胞。多个全基因组关联研究（GWAS）已经将IL-33和ST 2鉴定为 哮喘易感基因座该应用中的实验具有重要的临床相关性，因为NIH- 资助的严重哮喘研究项目（SARP）报道了PGI 2受体（称为PGI 2受体）的基因表达， PTGIR）是最能区分重度哮喘患者和 有轻微疾病和健康对照组。在SARP中，重度哮喘患者的哮喘发作率显着降低，但并非如此 PGI 2受体的基因表达。本申请的长期目标是确定 上皮细胞PGI 2受体表达降低与重度哮喘相关的机制 (Aim 1）并确定内源性PGI 2信号传导和外源性PGI 2抑制的分子机制 ILC 2增殖和功能（目的2）。研究内源性PGI 2的作用对于理解 环氧合酶抑制药物的作用，最广泛使用的一类非处方药 在世界上，对先天性过敏性免疫反应，因为这些药物抑制PGI 2的生产。调查 外源性PGI 2的作用对于理解吸入PGI 2或其类似物对肺动脉高压的潜在影响是重要的。 先天性过敏性免疫应答，因为这类药剂是FDA批准的，并且目前用于治疗 肺动脉高压，因此其用途可用于治疗过敏性呼吸道疾病， 哮喘。这些研究是范式转变，因为目前没有已知的FDA批准的阴性 空气过敏原诱导的IL-33释放的调节剂，我们的初步数据强烈支持PGI 2可能是 第一个描述。研究内源性PGI 2的作用对于理解 环加氧酶抑制药物，其中一个最广泛使用的类别的非处方药， 世界上，对先天性过敏性免疫反应，因为这些药物抑制PGI 2的生产。拟议 实验将推进这一领域，因为他们将定义PGI 2，一种FDA批准的药物，目前用于 肺动脉高压，控制早期先天性过敏性免疫反应。PGI 2的当前可用性 人类治疗突出了我们应用的临床意义，因为这种疗法可以立即 可转移到过敏性呼吸道疾病，如哮喘。

Allergic airway inflammation is a hallmark of asthma, one of the most common chronic diseases in the United States. The group 2 innate lymphoid cell (ILC2) is a recently described cell type that is a far more potent producer of IL-5 and IL-13 on a per cell basis than CD4+ Th2 cells, and there is increasing evidence that ILC2 are critical to the genesis and amplification of allergic inflammatory responses. In the last funding cycle of this VA Merit Award, we reported that prostaglandin (PG) I2 negatively regulates ILC2 function, both in vitro and in vivo, while inhibiting innate immunity-mediated airway eosinophilia, mucus metaplasia, and airways responsiveness, cardinal features of the asthma phenotype. Our novel in vivo preliminary data strongly suggests that PGI2 signaling inhibits Alt Ex-induced airway release of IL-33, an alarmin cytokine that binds to the ST2 receptor on ILC2 and other cells. Multiple genome wide association studies (GWAS) have identified IL-33 and ST2 as asthma susceptibility loci. The experiments in this application have important clinical relevance as the NIH- funded Severe Asthma Research Program (SARP) reported that gene expression for the PGI2 receptor (termed PTGIR) in epithelial brushings was among the genes to best differentiate patients with severe asthma from those with mild disease and healthy controls. In SARP, patients with severe asthma had significantly lower, but not absent) gene expression of the PGI2 receptor. The long-term objectives of this application are to determine the mechanisms by which decreased PGI2 receptor expression in the epithelium is associated with severe asthma (Aim 1) and define the molecular mechanisms by which endogenous PGI2 signaling and exogenous PGI2 inhibit ILC2 proliferation and function (Aim 2). Investigating the role of endogenous PGI2 is critical to understanding the effect of cyclooxygenase-inhibiting drugs, one of the most widely used classes of over-the-counter medications in the world, on the innate allergic immune response as these agents inhibit PGI2 production. Investigating the role of exogenous PGI2 is important to understand the potential effects of inhaled PGI2 or its analogs on the innate allergic immune response as such agents are FDA approved and currently used therapeutically for pulmonary hypertension, and therefore the use of which could be used to treat allergic respiratory diseases such as asthma. These studies are paradigm shifting because there are currently no known FDA approved negative regulators of aeroallergen-induced IL-33 release and our preliminary data strongly supports that PGI2 may be the first described. Investigating the role of endogenous PGI2 is critical to understanding the effect of cyclooxygenase-inhibiting drugs, one of the most widely used classes of over-the-counter medications in the world, on the innate allergic immune response as these agents inhibit PGI2 production. The proposed experiments will advance the field in that they will define how PGI2, an FDA approved agent currently used in pulmonary hypertension, controls the early innate allergic immune response. The current availability of PGI2 for human treatment highlights the clinical significance of our application, as this therapy could be immediately transferrable to allergic respiratory diseases such as asthma.