Oxidative Stress and Regional Airway Remodeling and Fibrosis in Obese Asthma

摘要 肥胖是哮喘的主要共病之一，也是哮喘的潜在调节因素，在美国，近40%的哮喘患者受到肥胖的影响。 并增加了它的严重性。肥胖型哮喘患者对传统抗炎疗法的反应不佳 与LEAN相比，针对哮喘的新生物制剂对肥胖哮喘患者的疗效较差。很少有研究 已经在肥胖的动物或肥胖的哮喘患者中进行了研究，导致了重大的知识缺失。 哮喘的一个关键特征是呼吸道重塑和纤维化，广义上定义为分布的改变， 患者与健康人气道壁结构成分的厚度、成分、质量或体积 病人。肥胖患者的气道重塑很难诊断为胸壁的机械改变 顺应性可能会导致所看到的生理变化。经典的，呼吸道重塑的证据和 肺功能测定显示纤维化为固定的呼吸道阻塞。然而，肺活量测定不仅对 外周气道，发生气道重塑，但从根本上不能定位 重塑和纤维化。因此，在研究呼吸道重塑和纤维化方面，一个关键的研究限制 哮喘正在定义疾病活动区，以探索疾病特有的机制。了解大自然 肥胖性哮喘的气道重塑和纤维化的研究以及快速筛选新疗法需要翻译 临床前模型和患者之间的联系，同时使用先进的成像技术。利用3D技术研究哮喘的最新研究进展 129Xe磁共振功能成像显示了可逆性和固定性换气缺陷的位置 (根据支气管扩张剂的响应度定义)。几项研究表明，固定的缺陷代表 呼吸道重塑和纤维化，但到目前为止，这是间接从痰分析和CT扫描推断出来的。 我们的中心假设是，129XeMRI上的异常换气部位代表了气道重塑的区域。 和纤维化，富含侵袭性、增殖性和致纤维化的成纤维细胞。我们进一步 假设氧化应激区域变化驱动转化生长因子-β的产生 (转化生长因子-β)直接促进成纤维细胞重塑。最后，我们假设129XeMRI将是一种敏感和 肥胖哮喘患者和肥胖哮喘大鼠模型中气道重塑和纤维化的特异性生物标志物。通过 利用我们在临床哮喘、支气管镜检查和细胞功能/信号转译方面的卓越专业知识 和3D磁共振成像，在患者和动物模型中，我们将进行体外细胞特异性机制 研究和活体动物模型研究揭示分子和细胞功能的机制 以下具体目标：目的1)确定病理、结构细胞特征(呼吸道成纤维细胞和上皮细胞 细胞)和氧化还原状态，对应于固定和可逆的支气管扩张剂后缺陷(BD)的区域 在肥胖哮喘患者中；2)确定氧化还原介导的转化生长因子-β信号在呼吸道之间的细胞需求 上皮细胞和成纤维细胞驱动肥胖性哮喘局部重构；3)发展非侵入性3D成像 肥胖哮喘实验性啮齿动物模型中评估呼吸道局部重塑的技术。

ABSTRACT Obesity, a major comorbidity and a potential modulator of asthma, affects nearly 40% of asthmatics in the U.S., and increases its severity. Obese asthmatics do not respond as well to conventional anti-inflammatory therapies and new biologics targeting asthma are less effective in obese asthmatics compared to lean. Very little research has been conducted in obese animals or obese asthmatics, resulting in a major knowledge deficit. A key feature of asthma is airway remodeling and fibrosis, broadly defined as a change in distribution, thickness, composition, mass or volume of structural components of the airway wall of patients relative to healthy patients. Airway remodeling is difficult to diagnose in obese patients as mechanical changes in chest wall compliance can contribute to the physiological changes seen. Classically, evidence of airway remodeling and fibrosis are revealed as fixed airway obstruction on spirometry. However, spirometry is not only insensitive to the peripheral airways, where airway remodeling occurs, but is fundamentally incapable of localizing the sites of remodeling and fibrosis. Thus, a critical research limitation in the study of airway remodeling and fibrosis in asthma is defining regions of disease activity to explore disease-specific mechanisms. To understand the nature of airway remodeling and fibrosis in obese asthma and to rapidly screen for novel therapies requires translation between preclinical models and patients, while using advanced imaging. Recent work in asthma using 3D functional imaging with 129Xe MRI has revealed the location of both reversible and fixed ventilation defects (defined based on bronchodilator responsivity). Several studies suggest that fixed defects represent sites of airway remodeling and fibrosis, but to date, this has been inferred indirectly from sputum analyses and CT scans. Our central hypothesis is that sites of abnormal ventilation on 129XeMRI represent areas of airway remodeling and fibrosis and are enriched with fibroblasts that are invasive, proliferative and fibrogenic. We further hypothesize that regional alterations in oxidant stress driving the production of transforming growth factor-beta (TGF-β) direct pro-remodeling fibroblast functions. Lastly, we hypothesize that 129XeMRI will be a sensitive and specific biomarker of airway remodeling and fibrosis in obese asthmatics and rat models of obese asthma. By leveraging our excellence in clinical asthma, bronchoscopy, and translational expertise in cell function/signaling and 3D MR imaging in both patients and animal models, we will conduct both ex vivo cell-specific mechanistic studies and in vivo animal model studies to uncover the mechanisms of molecular and cellular function through the following Specific Aims: Aim 1) Identify the pathology, structural cell profile (airway fibroblast and epithelial cell) and redox status corresponding to regional areas of fixed and reversible post-bronchodilator defects (BD) in obese asthmatics; 2) Define the cellular requirement for redox-mediated TGF-β signaling between airway epithelial cells and fibroblasts driving regional remodeling in obese asthma; 3) Develop non-invasive 3D imaging techniques to assess airway regional remodeling in experimental rodent models of obese asthma.