PGI2 regulation of TSLP-mediated allergic inflammation in the lung

PGI2 对 TSLP 介导的肺部过敏性炎症的调节

• 批准号: 9252828
• 负责人: Ray Stokes Peebles
• 金额: $ 35.68万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252828
• 关键词: Affect; Allergens; Allergic; Allergic inflammation; Alternaria; Animals; Arachidonic Acids; Asthma; Cell secretion; Cells; Chronic Disease; Data; Dendritic Cells; Development; Diet; Dietary Supplementation; Disease; Eosinophilia; Epithelial Cells; Epoprostenol; FDA approved; Fungal Antigens; Health; Hour; Human; Hypersensitivity skin testing; Immediate hypersensitivity; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-13; Interleukin-5; Laboratories; Lead; Link; Lung; Lung diseases; Lymphoid Cell; Mediating; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Mucous body substance; Mus; Omega-3 Fatty Acids; Ovalbumin; Pathway interactions; Patients; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Phase; Procedures; Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Proteins; Public Health; Publishing; Pulmonary Hypertension; Reaction; Reagent; Regulation; Respiratory physiology; Role; Signal Pathway; Signal Transduction; TSLP gene; Testing; Th2 Cells; United States; adaptive immunity; airborne allergen; airway inflammation; allergic airway inflammation; analog; clinically relevant; clinically significant; cytokine; effective therapy; fungus; hypertension control; in vivo; inhibitor/antagonist; intraperitoneal; microbial; microorganism antigen; mouse model; novel; research study; response

DESCRIPTION (provided by applicant): Allergic airway inflammation is a hallmark of asthma, a disease that is a significant cause of morbidity in the US. Group 2 innate lymphoid cells (ILC2) produce cytokines that drive the initial phase of allergic airway inflammation. ILC2 are activated by cytokines such as thymic stromal lymphopoietin (TSLP) that are produced in response to airway challenge with Alternaria alternata, a widespread fungal aeroallergen that has been linked to severe asthma exacerbations. To date, there are no known negative regulators of lung ILC2 that are approved by the FDA. However, our novel preliminary data reveals that endogenous PGI2 critically inhibits both airway TSLP expression and the lung expression of IL-5 and IL-13, cytokines expressed by lung ILC2, following intratracheal (IT) challenge of mice with the allergen extract of Alternaria alternata. Additional preliminary data suggests that exogenous PGI2 inhibits innate immune cell expression of TSLP in both mouse and human cells. These preliminary data lead us to propose the hypothesis that PGI2 negatively regulates the expression and signaling of TSLP in response to Alternaria airway challenge and, as a result, inhibits the development and function of lung ILC2. This proposal will determine how PGI2 regulates the activation of host innate immune cells and signaling pathways to the microbial antigens in Alternaria alternata that lead to allergic inflammatory responses. The proposed studies are paradigm shifting in that they will determine the role of PGI2 in blocking IL-5 and IL-13 expression by lung ILC2 and the signaling pathways responsible for this inhibition. These proposed studies are clinically relevant in that we will define potential mechanisms by which PGI2, which is currently FDA approved for the treatment of pulmonary hypertension, may be effective in the treatment of allergic airway inflammatory diseases such as asthma. In addition, we will define how dietary supplementation of ω-3 fatty acid, which reduces endogenous PGI2, regulates the early innate allergic immune response to Alternaria alternata challenge. Such diets have been recommended as asthma therapy, but our preliminary data leads us to hypothesize that ω-3 fatty acid dietary supplementation increases airway TSLP expression and lung ILC2 cell cytokine secretion, thus exacerbating allergic airway inflammation. The proposed studies will advance the field by defining mechanisms that negatively regulate the early innate immune response to the protease containing allergens such as Alternaria alternata.

描述（由申请人提供）：过敏性气道炎症是哮喘的标志，哮喘是美国发病率的重要原因。2组先天淋巴样细胞（ILC2）产生驱动过敏性气道炎症初始阶段的细胞因子。ILC2可被胸腺基质淋巴生成素（TSLP）等细胞因子激活，这些细胞因子是在交替孢霉（alternnaria alternata，一种广泛存在的真菌气致过敏原，与严重哮喘发作有关）气道挑战时产生的。迄今为止，还没有已知的经FDA批准的肺ILC2阴性调节剂。然而，我们新的初步数据显示，内源性PGI2严重抑制气道TSLP的表达和肺IL-5和IL-13的表达，肺IL-13是由肺ILC2表达的细胞因子，在气管内（IT）刺激了交替孢霉的过敏原提取物后。另外的初步数据表明，外源性PGI2抑制小鼠和人类细胞中TSLP的先天免疫细胞表达。这些初步数据使我们提出了PGI2负性调节TSLP的表达和信号传导以应对交替菌气道挑战，从而抑制肺ILC2的发育和功能的假设。这一提议将确定PGI2如何调节宿主先天免疫细胞的激活和导致过敏炎症反应的互交莲子微生物抗原的信号通路。拟议的研究是范式转换，因为它们将确定PGI2在通过肺ILC2阻断IL-5和IL-13表达中的作用以及负责这种抑制的信号通路。这些拟议的研究具有临床相关性，因为我们将确定PGI2的潜在机制，PGI2目前已被FDA批准用于治疗肺动脉高压，可能有效治疗过敏性气道炎症性疾病，如哮喘。此外，我们将确定膳食补充ω-3脂肪酸，其降低内源性PGI2，如何调节对交替稻瘟菌攻击的早期先天性过敏性免疫反应。此类饮食已被推荐用于哮喘治疗，但我们的初步数据使我们假设ω-3脂肪酸膳食补充会增加气道TSLP表达和肺ILC2细胞细胞因子分泌，从而加剧过敏性气道炎症。拟议的研究将通过定义对含有变应原的蛋白酶（如交替孢霉）的早期先天免疫反应进行负调节的机制来推进该领域。