T helper 2 Inflammation & Severe Muscularization of Arteries in the Lungs.

T 辅助 2 炎症

基本信息

批准号：
8505019
负责人：
Gabriele Grunig
金额：
$ 37.7万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8505019
关键词：
Ablation Acute Address Adoptive Transfer Affect Antibodies Antigens Arterial Injury Arteries Asthma Autoimmune Diseases Biological Response Modifiers C57BL/6 Mouse CD4 Positive T Lymphocytes Cells Childhood Chimeric Proteins Cigarette Smoker Clinical Data Companions Complement Complex Data Dendritic Cells Development Diagnosis Diphtheria Toxin Dirofilaria immitis Disease Evolution Goals Heart Helminths Human Hypertrophy Hypoxia ITGAX gene Immune Immune System Diseases Immune response Immunity Impairment Incidence Individual Infection Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Interleukin-1 Interleukin-13 Interleukin-17 Interleukin-4 Interleukins Laboratories Lesion Life Cycle Stages Lung Lung Inflammation Measurement Mediating Mediator of activation protein Mus Parasites Parasitic Diseases Parasitic infection Pathology Patients Phase Process Production Pulmonary Hypertension Pulmonary artery structure Recombinant Interleukin-13 Right Ventricular Function Role Scleroderma Severities Smooth Muscle Myocytes Systemic Scleroderma Systolic Pressure T cell response T-Lymphocyte Techniques Testing Time Transgenic Mice Ventricular Viral Wild Type Mouse Work abstracting arterial remodeling bronchial artery cytokine diphtheria toxin receptor hemodynamics member mortality mouse model outcome forecast promoter public health relevance pulmonary arterial hypertension receptor research study response time interval

项目摘要

DESCRIPTION (provided by applicant): T helper 2 Inflammation & Severe Muscularization of Arteries in the Lungs Project Summary / Abstract Pulmonary arterial remodeling, characterized by severe muscularization, is commonly seen in infections with helminth parasites that spend part of their life cycle in the pulmonary artery (e.g. Dirofilaria immitis). These parasites induce a T helper 2 (Th2) response. This same type of lesion is also seen in the bronchial artery in asthma, another Th2-response associated disease, particularly in individuals with asthma of long duration, or in asthmatic cigarette smokers. These associations indicate that severe muscularization of the pulmonary or bronchial arteries might be a consequence of a Th2 driven inflammation. Classically, severe pulmonary arterial muscularization has been described in pulmonary arterial hypertension (PAH). An immune-pathology has been suspected in PAH associated with autoimmune diseases such as systemic scleroderma, viral, or parasitic diseases. In preliminary experiments, we have shown that the Th2 response to soluble antigen alone is sufficient to induce severe pulmonary arterial muscularization and increased right ventricular systolic pressures following acute hypoxia. This was induced in immunized C57BL/6 mice that were given intermittent airway challenges over a prolonged period of time with either of two different antigens. CD4+ T cells and Interleukin (IL)-4 were necessary for the development of pulmonary arterial muscularization and transient depletion of an important Th2 cytokine, IL-13, decreased the severity of the lesion. IL-13 alone was not sufficient indicating that a complex Th2 - initiated process induced severe arterial muscularization. Which components of the Th2 response directly cause the arterial muscularization and how the Th2 response components interact are important questions yet to be answered. To address these questions, three specific aims are proposed to identify the roles of T cells and dendritic cells (DCs) and soluble immune mediators (IL-17, IL-33) for the effector phase during which arterial muscularization occurs. Experiments are proposed to deplete or to adoptively transfer T cells, dendritic cells, and soluble immune mediators during the time periods that arterial injury and remodeling occur in the lungs. Using techniques that are securely established in my laboratory, the hypothesis to be tested is that T cells and DCs control the production of IL-17 and IL-33 thereby directly determining the degree of pulmonary arterial muscularization and right ventricular function. The long range goal of this work takes advantage of the mouse model developed in my laboratory to identify targets for the diagnosis, prognosis and management for inflammation associated PAH, such as PAH seen in scleroderma patients. This is unique and significant because a large body of clinical data has suspected the involvement of the immune response, but has not yet dissected the causal relationship between the immune response and severe muscularization of arteries in the lungs.

描述（由申请人提供）：T助手2炎症和肺部动脉的严重肌肉化摘要 /抽象的肺动脉重塑，特征是以严重的肌肉化为特征动脉（例如二脂脂免疫炎）。这些寄生虫诱导T助手2（TH2）响应。在哮喘的支气管动脉中也可以看到这种类型的病变，这是另一种Th2反应相关的疾病，特别是在持续时间长的哮喘患者或哮喘吸烟者中。这些关联表明，肺动脉或支气管动脉的严重肌肉化可能是TH2驱动的炎症的结果。从经典上讲，在肺动脉高压（PAH）中已经描述了严重的肺动脉肌肉化。怀疑与自身免疫性疾病（例如全身性硬皮病，病毒或寄生虫病）相关的PAH中有一种免疫病理学。在初步实验中，我们已经表明，仅对可溶性抗原的Th2反应足以诱导严重的肺动脉肌肉化并增加急性缺氧后右心收缩压。这是在免疫的C57BL/6小鼠中引起的，这些小鼠在长时间内与两种不同的抗原中的任何一个都给予间歇性气道挑战。 CD4+ T细胞和白介素（IL）-4对于发展重要的Th2细胞因子IL-13的肺动脉肌肉化和瞬时耗竭所必需，这降低了病变的严重程度。仅IL -13就不足以表明复杂的TH2启动过程会引起严重的动脉肌肉化。 TH2响应的哪些组成部分直接引起动脉肌肉化以及TH2响应组件如何相互作用是尚待回答的重要问题。为了解决这些问题，提出了三个特定的目的，以确定T细胞和树突状细胞（DC）和可溶性免疫介质（IL-17，IL-33）在发生动脉肌肉化的效应阶段的作用。提议在肺部发生动脉损伤和重塑的时期内，提出实验以耗尽或传递T细胞，树突状细胞和可溶性免疫介质。使用在我的实验室中牢固确定的技术，要检验的假设是T细胞和DC控制IL-17和IL-33的产生，从而直接确定肺动脉肌肉化和右心室功能的程度。这项工作的远距离目标利用了我的实验室中开发的小鼠模型，以识别与炎症相关的PAH的诊断，预后和管理的靶标，例如在硬皮病患者中看到的PAH。这是独特而重要的，因为大量临床数据已经怀疑免疫反应的参与，但尚未剖析肺部动脉的免疫反应与严重的动脉肌肉化之间的因果关系。