Vasculopathy and Systemic Sclerosis-Associated Interstitial Lung Disease

项目总结/摘要 系统性硬化症（SSc）是一种以血管病变为特征的全身性自身免疫性风湿性疾病， 炎症和纤维化，并且在所有全身性自身免疫性疾病中具有最高的病例特异性死亡率。 风湿性疾病间质性肺病（ILD），一组密切相关的肺部疾病，其特征为 40-60%的成年SSc患者存在非感染或瘤形成引起的肺泡炎症、损伤和纤维化 并且是该人群中死亡和住院的主要原因。SSc-ILD的治疗是有限的， 并且没有研究测试干预措施以预防SSc-ILD的发展。血管病变是 SSc及其最早的表现之一。我们假设内皮损伤和微血管损伤 是SSc-ILD发病机制中的关键激发事件，因此是潜在的新型治疗靶点 预防SSc-ILD。本提案的总体目标是阐明以下方面之间的关系： SSc成人患者的肺和外周微血管、内皮功能、肺功能和ILD。 我们将对100名患有SSc的成年人进行前瞻性队列研究， 功能和分子方法来了解血管室如何有助于 在SSc中发展ILD。在目标1中，我们将量化肺微血管灌注血容量， SSc和SSc-ILD，并确定其与外周微血管结构和肺功能的关系。在Aim中 2、我们将比较SSc伴和不伴ILD患者的外周微血管内皮功能 并确定外周微血管内皮功能与肺功能的关系 微血管灌注、外周微血管结构和肺功能。在目标3中， 将对循环内皮细胞进行单细胞RNA测序，以揭示分子机制， 区分SSc成人和SSc-ILD成人。我们的研究有可能产生范例- 改变结果，这将（1）改变我们概念化假定的因果关系的方式， SSc中的微血管疾病和ILD，（2）确定用于SSc-ILD临床试验的新结局指标， 和（3）使我们能够开发新的治疗方法，用于SSc-ILD的一级和二级预防。我们 预期本研究的结果将为其他纤维化肺病提供信息并适用于其他纤维化肺病，从而 为新的治疗方法铺平了道路。

Project Summary/Abstract Systemic sclerosis (SSc) is a systemic autoimmune rheumatic disease characterized by vasculopathy, inflammation, and fibrosis, and has the highest case specific mortality rate of all systemic autoimmune rheumatic diseases. Interstitial lung disease (ILD), a closely related group of lung disorders characterized by alveolar inflammation, injury, and fibrosis not due to infection or neoplasia, affects 40-60% of adults with SSc and is the primary cause of death and hospitalization in this population. Treatments for SSc-ILD are limited, and no studies have tested interventions to prevent the development of SSc-ILD. Vasculopathy is a hallmark of SSc and one of its earliest manifestations. We hypothesize that endothelial damage and microvascular injury are critical inciting events in the pathogenesis of SSc-ILD, and are therefore potential novel treatment targets for the prevention of SSc-ILD. The overarching goal of this proposal is to elucidate the relationships between the pulmonary and peripheral microvasculature, endothelial function, lung function, and ILD in adults with SSc. We will perform a prospective cohort study of 100 adults with SSc in which we will combine structural, functional, and molecular approaches to understand how the vascular compartment contributes to the development of ILD in SSc. In Aim 1, we will quantify the pulmonary microvascular perfused blood volume in SSc and SSc-ILD and determine its relationship to peripheral microvascular structure and lung function. In Aim 2, we will compare peripheral microvascular endothelial function between SSc patients with and without ILD and determine the relationship between peripheral microvascular endothelial function and pulmonary microvascular perfusion, peripheral microvascular structure, and lung function in adults with SSc. In Aim 3, we will perform single cell RNA sequencing of circulating endothelial cells to uncover the molecular mechanisms that distinguish adults with SSc from those with SSc-ILD. Our study has the potential to generate paradigm- shifting results that will (1) change the way we conceptualize the putative causal relationship between microvascular disease and ILD in SSc, (2) identify novel outcome measures for use in SSc-ILD clinical trials, and (3) enable us to develop new treatments for the primary and secondary prevention of SSc-ILD. We anticipate that the results of this study will inform and be applicable to other fibrotic lung diseases, thereby paving the way toward novel therapeutic approaches.