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

描述(由申请人提供)：T Helper 2肺部动脉的炎症和严重肌化项目摘要/摘要肺动脉重塑，以严重的肌化为特征，通常见于感染了蠕虫寄生虫的感染，这些寄生虫的部分生命周期在肺动脉中度过(例如，双丝虫肺炎)。这些寄生虫诱导T辅助细胞2(Th2)反应。同样类型的病变也见于哮喘的支气管动脉，这是另一种与Th2反应相关的疾病，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化可能是Th2驱动的炎症的结果。传统上，严重的肺动脉肌化已被描述为肺动脉高压(PAH)。PAH与系统性硬皮病、病毒或寄生虫病等自身免疫性疾病相关，已被怀疑是一种免疫病理。在初步实验中，我们已经证明，单是Th2对可溶性抗原的反应就足以诱导严重的肺动脉肌化和急性缺氧后右室收缩压的增加。这是在免疫的C57BL/6小鼠身上诱导的，这些小鼠在很长一段时间内受到两种不同抗原中的任何一种的间歇性呼吸道攻击。CD4+T细胞和白介素4是发展肺动脉肌化所必需的，而重要的Th2细胞因子IL-13的短暂耗竭可以减轻病变的严重程度。单靠IL-13是不够的，这表明Th2启动的复杂过程诱导了严重的动脉肌化。Th2反应的哪些成分直接导致动脉肌化以及Th2反应成分如何相互作用是有待回答的重要问题。为了解决这些问题，提出了三个特定的目标，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)在动脉肌化发生的效应期中的作用。建议进行实验，以耗尽或过继转移T细胞、树突状细胞和可溶性免疫介质，在肺内发生动脉损伤和重塑的时间段。使用在我的实验室安全建立的技术，要检验的假设是T细胞和DC控制IL-17和IL-33的产生，从而直接决定肺动脉肌化的程度和右心功能。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PAH的诊断、预后和管理的靶点，例如硬皮病患者中看到的PAH。这是独一无二的，意义重大，因为大量临床数据怀疑免疫反应参与其中，但尚未剖析免疫反应与肺部动脉严重肌化之间的因果关系。 公共卫生相关性：肺中动脉的炎症和严重的肌肉化项目简介肺动脉肌化是一种常见的组织学损害，可见于肺动脉高压(PAH)。严重的动脉肌化也是与辅助性T细胞2型(Th2)免疫反应相关的疾病的典型表现：蠕虫寄生虫感染、影响肺动脉的自身免疫性疾病以及影响支气管动脉的哮喘。在我们之前工作的基础上，我们开发了Th2免疫反应诱导的严重肺动脉肌化的小鼠模型，该提议试图确定T细胞反应控制的细胞和介质，这些细胞和介质是治疗与严重炎症性疾病相关的肺动脉高压的新靶点，例如由自身免疫引起的。

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. PUBLIC HEALTH RELEVANCE: T helper 2 inflammation & severe muscularization of arteries in the lungs Project Narrative Pulmonary arterial muscularization is a frequent histological lesion seen in pulmonary arterial hypertension (PAH). Severe arterial muscularization is also typical for diseases associated with T helper 2 (Th2) immune responses: helminth parasite infections, auto-immune diseases affecting pulmonary arteries and asthma affecting bronchial arteries. Building on our previous work developing Th2-immune-response induced mouse models of severe pulmonary arterial muscularization, this proposal seeks to identify T cell response controlled cells and mediators that are new targets for the management of pulmonary hypertension associated with severe inflammatory diseases caused for example by auto-immunity.