Muscularization of pulmonary arteries induced by an adaptive immune response

适应性免疫反应诱导的肺动脉肌化

基本信息

批准号：
7844971
负责人：
Gabriele Grunig
金额：
$ 23.24万
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：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7844971
关键词：
Ablation Alleles Antigens Appearance Arteries Autoantibodies Autoimmune Process Blood Vessels Breathing CD4 Positive T Lymphocytes Cell Count Cell Culture Techniques Cell Proliferation Cell physiology Cells Chronic Clinical Communicable Diseases Companions Complement Correlation Studies Data Development Endothelial Cells Enhancers Epithelial Etiology Generations Genetic Enhancer Element Goals Helminths Histocompatibility Antigens Class II Histologic Homologous Gene Human Hyperplasia Hypertrophy Hypoxia ITGAM gene Immune Immune System Diseases Immune response In Situ In Vitro Incidence Infection Injury Interleukin-13 Interleukin-4 Interleukins Lesion Leukocytes Life Expectancy Lung Maps Mediator of activation protein Mesenchymal Mitogens Molecular Morphology Mus Myeloid Cells Parasites Pathogenesis Patients Process Proliferating Proliferation Marker Pulmonary artery structure Quality of life Role Route Schistosome Parasite Severities Smooth Muscle Smooth Muscle Myocytes Specificity Testing Time Transgenic Mice Work abstracting antigen challenge arterial remodeling cell type cytokine fighting filaria monocyte mouse model precursor cell promoter public health relevance pulmonary arterial hypertension receptor research study resistin response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Muscularization of pulmonary arteries induced by an adaptive immune response Abstract Pulmonary arterial hypertension (PAH) is a devastating condition because of its deleterious impact on quality of life, and life expectancy. Clinical correlation studies have suggested an immune pathogenesis because of the increased incidence of PAH in autoimmune and infectious diseases. Helminth infections can also cause PAH, but direct injury by the migrating parasites to the arteries has been thought to be the major cause of arterial remodeling. Pulmonary arterial remodeling associated with smooth muscle cell hyperplasia is frequently seen in PAH. In preliminary experiments, severe pulmonary arterial muscularization was induced by intermittent antigen challenge for a prolonged period of time via the inhaled route in primed mice. Essential roles for CD4+ T cells, the antigen- specific T helper (Th)2 response, and a pathogenic Th2 cytokine [Interleukin (IL) 13] in inducing severe pulmonary arterial musularization were identified. This indicated that the host's immune response developed to fight helminth infections alone is sufficient to induce severe pulmonary arterial muscularization, even without the presence of parasites. The severity of arterial remodeling was highly significantly correlated with the numbers of cells that bordered pulmonary arteries and expressed resistin-like molecule (RELM)1. RELM1 is known as a smooth muscle cell mitogen, induced by Th2 responses and by chronic hypoxia. But the role of RELM1 in pulmonary arterial remodeling has not been experimentally tested. The preliminary data show that the majority of proliferation marker positive cells within the remodeled pulmonary arteries had the appearance of endothelial cells and neo-intima cells. Few cells with smooth muscle morphology were proliferation marker positive. These data indicate that the origin of the cells within the remodeled pulmonary arteries might not be smooth muscle cells. The long range goal of this proposal is to understand how the Th2 immune response induces pulmonary arterial muscularization. To accomplish this goal, specific aims are proposed to identify the origin of the cells that populate the remodeled pulmonary arteries and to define the role of RELM1. The experimental approach will be to study mice that carry fluorescent tags driven by cell-type specific promoters for endothelial cells, leukocytes, and monocytes / myeloid cells, and RELM1 KO mice. Studies with mice that express receptors that can be used for cell ablation, and in vitro cell culture will be used for mechanistic analysis. The working hypothesis is that precursor cell proliferation followed by differentiation into smooth muscle cells and RELM1 are essential contributors to Th2-response-induced pulmonary arterial remodeling. PUBLIC HEALTH RELEVANCE: Muscularization of pulmonary arteries induced by an adaptive immune response Relevance: Pulmonary arterial hypertension (PAH) is a devastating condition that can accompany chronic parasite infections and auto-immune diseases. Thickening of the walls of pulmonary arteries by layers of smooth muscle cells is one of the typical morphological alterations seen in PAH and this process is a target for the development of new treatment strategies. The proposed studies are aimed at delineating the cellular origin and mediators that cause the accumulation of these smooth muscle cells in a mouse model of severe pulmonary arterial remodeling induced by the adaptive immune response.

描述（由申请人提供）：由自适应免疫反应引起的肺动脉肌肉化抽象肺动脉高压（PAH）是一种毁灭性的疾病，因为它对生活质量和预期寿命具有有害影响。临床相关研究表明，由于自身免疫性和感染性疾病的PAH发生率增加，因此存在免疫发病机理。蠕虫感染也可能引起PAH，但是迁移到动脉的直接伤害被认为是动脉重塑的主要原因。与平滑肌细胞增生相关的肺动脉重塑经常在PAH中看到。在初步实验中，通过吸入的小鼠中的吸入途径长时间，通过间歇性抗原挑战诱导了严重的肺动脉肌肉。 CD4+ T细胞，抗原特异性T辅助器（Th）2反应和致病性Th2细胞因子[白介素（IL）13]在诱导严重的肺动脉动动肌肉中的基本作用。这表明，即使不存在寄生虫，宿主的免疫反应就足以抗击蠕虫感染。动脉重塑的严重程度与接壤的肺动脉和表达抗蛋白样分子（RERM）1的细胞数量高度显着相关。 RERM1被称为平滑肌细胞有丝分裂原，由Th2反应和慢性缺氧诱导。但是RERM1在肺动脉重塑中的作用尚未进行实验测试。初步数据表明，重塑的肺动脉中的大多数增殖标记阳性细胞具有内皮细胞和新内膜细胞的出现。很少有平滑肌形态的细胞为增殖标记阳性。这些数据表明，重塑肺动脉内细胞的起源可能不是平滑肌细胞。该提议的远距离目标是了解Th2免疫反应如何诱导肺动脉肌肉化。为了实现这一目标，提出了特定的目的来识别填充重塑肺动脉的细胞的起源并定义RERM1的作用。实验方法是研究携带由细胞类型的荧光标签的小鼠，由细胞类型的启动子驱动，白细胞和单核细胞 /髓样细胞以及RELM1 KO小鼠。使用可用于细胞消融的表达受体和体外细胞培养的小鼠的研究将用于机械分析。工作假设是前体细胞增殖，然后分化为平滑肌细胞，而RERM1是造成Th2反应诱导的肺动脉重塑的重要因素。公共卫生相关性：由适应性免疫反应引起的肺动脉的肌肉化相关性：肺动脉高压（PAH）是一种毁灭性的疾病，可以伴随慢性寄生虫感染和自身免疫性疾病。平滑肌细胞的肺动脉壁增厚是PAH中看到的典型形态变化之一，此过程是开发新治疗策略的目标。拟议的研究旨在描述细胞来源和介体，这些细胞起源和介体在由自适应免疫反应引起的严重肺动脉动脉重塑的小鼠模型中导致这些平滑肌细胞的积累。