Evaluating the Impact of Metabolic Dysfunction on Asthma Pathology and Physiology

项目概要/摘要： 超过40%的美国成年人肥胖，肥胖在严重哮喘患者中很常见。的 肥胖和严重哮喘之间的联系机制尚不清楚，但这是一个线索， 来自肥胖的代谢后果，包括胰岛素抵抗和全身性白细胞介素-6 炎症我们最近发现，一部分肥胖哮喘患者存在代谢功能障碍（MD）， 患有MD的肥胖患者比不患有MD的肥胖患者哮喘更严重。此外，我们还发现， 肥胖者肺功能降低与MD的相关性比与体重的相关性更强 指数.此外，我们发现，肥胖的MD患者对吸入性和全身性药物的反应很差， 皮质类固醇所有这些发现使我们假设肥胖相关的MD和胰岛素抵抗导致 导致皮质类固醇抵抗性气道功能障碍的气道病理学。在这里，我们打算测试一下 通过全面描述肥胖哮喘患者气道生理和病理学特征， MD和探索胰岛素介导气道功能障碍的机制。我们有三个目标：目标1 描述伴有和不伴有代谢异常的肥胖哮喘患者的放射学和生理学异常 功能障碍（MD）。在这里，我们将分析计算机断层扫描肺部扫描，并进行心肺运动 在患有和不患有MD的哮喘患者中进行测试。我们假设MD患者的放射学检查 测量支气管壁厚度和空气滞留，并在运动过程中遭受动态过度充气 练习不宽容。目的2将描述哮喘患者的气道炎症和气道重塑 在这里，我们将使用转录组学方法绘制MD哮喘患者的细胞谱， 从诱导痰样本中获得的轮廓，并从支气管内测量基底膜区厚度 活检样本来检验我们的假设，即肥胖MD患者的气道炎症是2型低， 这些患者具有以上皮下纤维化为特征的气道重塑。Aim 3将开发基因 胰岛素相关气道疾病的特征，并确定这些特征是否在哮喘患者中上调 胰岛素抵抗在这里，我们将利用体外细胞培养和空间转录组学来鉴定基因 胰岛素介导的气道疾病在气道成纤维细胞和上皮细胞中的表达特征。然后我们将 确定这些基因标记是否在哮喘患者的气道上皮刷毛或痰细胞中上调 这些目标将有助于解决有关疾病知识的重要空白 在严重哮喘的肥胖患者中起作用的机制，并有望提供数据， 为这些患者提供治疗方法。

Project Summary/Abstract: More than 40% of adult Americans are obese and obesity is common among patients with severe asthma. The mechanisms underlying the association between obesity and severe asthma are poorly understood, but a clue comes from the metabolic consequences of obesity, which include insulin resistance and systemic interleukin-6 inflammation. We recently showed that a subset of obese asthma patients have metabolic dysfunction (MD) and that obese patients with MD have more severe asthma than obese patients without MD. In addition, we found that lower lung function in obesity is more strongly related to measures of MD than measures of body mass index. Furthermore, we found that obese patients with MD respond poorly to inhaled and systemic corticosteroids. All of these findings lead us to hypothesize that obesity-related MD and insulin resistance causes airway pathology that leads to corticosteroid resistant airway dysfunction. Here, we propose to test this hypothesis by comprehensively characterizing airway physiology and pathology in obese asthma patients with MD and exploring mechanisms by which insulin mediates airway dysfunction. We have 3 aims: Aim 1 will characterize the radiographic and physiologic abnormalities in obese asthma patients with and without metabolic dysfunction (MD). Here we will analyze computed tomography lung scans and perform cardiopulmonary exercise testing in asthma patients with and without MD. We hypothesize that patients with MD have radiographic measures of bronchial wall thickness and air trapping and suffer dynamic hyperinflation during exercise leading to exercise intolerance. Aim 2 will characterize airway inflammation and airway remodeling in asthma patients with metabolic dysfunction; Here, we will map the cellular profile of asthma patients with MD using transcriptomic profiles from induced sputum samples and measure basement membrane zone thickness from endobronchial biopsy samples to test our hypothesis that airway inflammation in obese patients with MD is type-2 low and that these patients have airway remodeling characterized by subepithelial fibrosis. Aim 3 will develop gene signatures of insulin-related airway disease and determine if these signatures are upregulated in asthma patients with insulin resistance. Here we will utilize in vitro cell cultures and spatial transcriptomics to identify gene expression signatures of insulin-mediated airway disease in airway fibroblasts and epithelial cells. We will then determine if these gene signatures are upregulated in airway epithelial brushings or sputum cells from asthma patients with IR. Together these aims will help address an important gap in knowledge about disease mechanisms operating in obese patients with severe asthma and promises to provide data to inform novel treatment approaches for these patients.