Muscularization of pulmonary arteries induced by an adaptive immune response

摘要肺动脉高压（PAH）是一种毁灭性的疾病，因为它对生活质量和预期寿命有有害的影响。临床相关研究表明，多环芳烃在自身免疫性疾病和感染性疾病中的发病率增加可能与免疫机制有关。寄生虫感染也可引起多环芳烃，但迁移的寄生虫对动脉的直接损伤被认为是动脉重塑的主要原因。肺动脉重塑伴平滑肌细胞增生常见于肺动脉高压。在初步实验中，通过吸入途径对小鼠进行长时间的间歇性抗原刺激，诱导严重的肺动脉肌肉化。确定了CD4+ T细胞、抗原特异性T辅助（Th）2反应和致病性Th2细胞因子[白细胞介素（IL） 13]在诱导严重肺动脉肌肉化中的重要作用。这表明，即使没有寄生虫的存在，宿主为对抗寄生虫感染而产生的免疫反应也足以诱导严重的肺动脉肌肉化。动脉重塑的严重程度与肺动脉边缘细胞数量和表达抵抗素样分子（RELM）1高度显著相关。RELM1被认为是平滑肌细胞有丝分裂原，由Th2反应和慢性缺氧诱导。但RELM1在肺动脉重塑中的作用尚未得到实验证实。初步数据显示，肺动脉重构后的增生标志物阳性细胞多数具有内皮细胞和新生内膜细胞的形态。少数平滑肌形态细胞增殖标志物阳性。这些数据提示肺动脉重构内的细胞来源可能不是平滑肌细胞。这项建议的长期目标是了解Th2免疫反应如何诱导肺动脉肌肉化。为了实现这一目标，我们提出了确定重建肺动脉细胞的来源和确定RELM1的作用的具体目标。实验方法将是研究携带由内皮细胞、白细胞、单核细胞/髓细胞和RELM1 KO小鼠的细胞类型特异性启动子驱动的荧光标签的小鼠。表达受体的小鼠研究可用于细胞消融，体外细胞培养将用于机制分析。工作假设是，前体细胞增殖随后分化为平滑肌细胞和RELM1是th2反应诱导的肺动脉重塑的重要贡献者。相关性：肺动脉高压（PAH）是一种毁灭性的疾病，可伴随慢性寄生虫感染和自身免疫性疾病。肺动脉壁被平滑肌细胞层增厚是PAH中典型的形态学改变之一，这一过程是开发新的治疗策略的目标。提出的研究旨在描绘细胞起源和介质，导致这些平滑肌细胞的积累，在小鼠模型严重肺动脉重构诱导的适应性免疫反应。

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.