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

项目摘要/摘要肺动脉重塑以严重的肌肉化为特征，常见于部分生命周期在肺动脉内度过的寄生虫感染（如免疫Dirofilaria immitis）。这些寄生虫诱导辅助性T - 2 （Th2）反应。哮喘（另一种与th2反应相关的疾病）的支气管动脉也可见相同类型的病变，特别是在长期哮喘患者或哮喘吸烟者中。这些关联表明，肺或支气管动脉的严重肌肉化可能是Th2驱动的炎症的结果。典型地，严重的肺动脉肌肉化已被描述为肺动脉高压（PAH）。免疫病理被怀疑与自身免疫性疾病如系统性硬皮病、病毒性疾病或寄生虫病相关的多环芳烃。在初步实验中，我们已经表明，仅对可溶性抗原的Th2反应就足以诱导急性缺氧后严重的肺动脉肌肉化和右心室收缩压升高。这是在免疫的C57BL/6小鼠中诱导的，这些小鼠在长时间内用两种不同抗原中的任何一种给予间歇性气道刺激。CD4+ T细胞和白细胞介素(IL)-4对于肺动脉肌肉化的发展是必需的，一种重要的Th2细胞因子IL-13的短暂耗尽降低了病变的严重程度。单独IL-13不足以表明复杂的Th2启动过程诱导了严重的动脉肌肉化。哪些Th2反应成分直接导致动脉肌肉化，以及Th2反应成分如何相互作用是尚未回答的重要问题。为了解决这些问题，我们提出了三个特定的目标来确定T细胞和树突状细胞（dc）以及可溶性免疫介质（IL-17, IL-33）在动脉肌肉化发生的效应期的作用。在肺动脉损伤和重塑发生的时间段内，提出了消耗或过继转移T细胞、树突状细胞和可溶性免疫介质的实验。使用在我的实验室安全建立的技术，要测试的假设是T细胞和dc控制IL-17和IL-33的产生，从而直接决定肺动脉肌肉化程度和右心室功能。这项工作的长期目标是利用我实验室开发的小鼠模型来确定炎症相关多环芳烃的诊断、预后和管理靶点，例如硬皮病患者的多环芳烃。这是独特而重要的，因为大量的临床数据已经怀疑免疫反应的参与，但尚未解剖免疫反应和肺部动脉严重肌肉化之间的因果关系。

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.