Evaluating the Impact of Metabolic Dysfunction on Asthma Pathology and Physiology

项目摘要/摘要： 超过40%的美国成年人患有肥胖症，肥胖在患有严重哮喘的患者中很常见。这个 肥胖症和严重哮喘之间的联系机制尚不清楚，但有一条线索 来自肥胖的代谢后果，包括胰岛素抵抗和系统性白介素6 发炎。我们最近发现，肥胖哮喘患者的一部分患有代谢功能障碍(MD)和 有MD的肥胖患者比无MD的肥胖患者有更严重的哮喘。另外，我们发现， 肥胖者较低的肺功能与测量MD比测量体重的相关性更强 指数。此外，我们发现肥胖的MD患者对吸入和全身反应很差。 皮质类固醇。所有这些发现都让我们假设，肥胖相关的MD和胰岛素抵抗导致 导致皮质类固醇抵抗型呼吸道功能障碍的呼吸道病理。在这里，我们建议对此进行测试 肥胖性哮喘患者的呼吸道生理和病理综合特征假说 MD和探索胰岛素介导呼吸道功能障碍的机制。我们有三个目标：目标1将 有代谢和无代谢的肥胖性哮喘患者的X线和生理异常特征 功能障碍(MD)。在这里，我们将分析计算机断层扫描肺扫描和进行心肺锻炼 对患有和不患有MD的哮喘患者进行检测。我们假设MD患者有放射学检查 运动引导时支气管壁厚度和空气滞留的测量及动态过度充气 来锻炼自己的不宽容。AIM 2将描述哮喘患者的气道炎症和气道重塑 代谢障碍；在这里，我们将使用转录转录技术绘制患有MD的哮喘患者的细胞图谱 诱导痰标本的分布和支气管内膜基底膜厚度的测量 活检样本来验证我们的假设，即肥胖的MD患者的呼吸道炎症是低的，并且 这些患者有以上皮下纤维化为特征的气道重塑。AIM 3将开发基因 胰岛素相关呼吸道疾病的特征，并确定这些特征在哮喘患者中是否上调 患有胰岛素抵抗。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 胰岛素介导的呼吸道疾病在呼吸道成纤维细胞和上皮细胞中的表达特征。到时候我们会的 确定这些基因信号是否在哮喘的呼吸道上皮刷或痰细胞中上调 IR患者。这些目标加在一起将有助于解决有关疾病知识的一个重要差距。 肥胖症重度哮喘患者的作用机制并承诺提供数据为新的 这些患者的治疗方法。

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.