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PGI2 inhibition of pulmonary innate allergic immune responses

PGI2 抑制肺部先天过敏性免疫反应

基本信息

批准号：
9924242
负责人：
Ray Stokes Peebles
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-10-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924242
关键词：
Agonist Allergens Allergic Allergic Disease Allergic inflammation Allergic rhinitis Alternaria Antiinflammatory Effect Arachidonic Acids Asthma Award Binding Cell Proliferation Cell physiology Cells Cellular Structures Chronic Disease Data Development Disease Eosinophilia Epithelial Epithelial Cells Epithelium Epoprostenol Extrinsic asthma FDA approved Funding Fungal Antigens Gene Expression Genes Glucocorticoids Human Hypersensitivity skin testing IL2RA gene IRF4 gene Immediate hypersensitivity Immune response In Vitro Inflammatory Inflammatory Response Inhalation Interleukin-13 Interleukin-2 Interleukin-5 Interleukin-9 Lead Link Lung Lung diseases Lymphoid Cell Mediating Metabolic Metabolism Metaplasia Military Personnel Modeling Molecular Morbidity - disease rate Mucous body substance Mus Natural Immunity Pathway interactions Patients Persons Pharmaceutical Preparations Phase Phenotype Prevalence Production Prostaglandin-Endoperoxide Synthase Proteins Public Health Pulmonary Hypertension Reaction Regulation Reporting Research Role STAT1 gene Signal Transduction Smooth Muscle Susceptibility Gene Testing Th2 Cells Therapeutic Uses United States United States National Institutes of Health Veterans adaptive immunity airborne allergen airway epithelium allergic airway inflammation analog asthma exacerbation bronchial epithelium cell type clinically relevant clinically significant constriction cytokine effective therapy experimental study genome wide association study hypertension control in vivo inhibitor/antagonist intraperitoneal microbial novel programs reagent testing receptor receptor expression

项目摘要

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.

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