Oxidative Stress and Regional Airway Remodeling and Fibrosis in Obese Asthma

肥胖哮喘的氧化应激、局部气道重塑和纤维化

• 批准号: 10240405
• 负责人: Loretta G Que
• 金额: $ 74.65万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240405
• 关键词: 3-Dimensional; Admission activity; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Area; Asthma; Automobile Driving; Biological; Biological Assay; Biological Markers; Bronchodilator Agents; Bronchoscopy; Cell Culture Techniques; Cell physiology; Cells; Cellular Structures; Chest wall structure; Clinical; Defect; Diagnosis; Disease; Disease Progression; Disease model; Epithelial Cells; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Functional Imaging; Goals; Histopathology; Image; Imaging Techniques; Inhalation; Knowledge; Location; Magnetic Resonance Imaging; Mechanics; Mediating; Modeling; Molecular; Monitor; Nature; Obesity; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathologic; Pathology; Patients; Peripheral; Phenotype; Physiological; Population; Pre-Clinical Model; Production; Protein Secretion; Rapid screening; Rattus; Research; Rodent Model; Sampling; Severities; Signal Transduction; Site; Spirometry; Sputum; Structure; Study models; Therapeutic Intervention; Thick; Thinness; Three-Dimensional Imaging; Transforming Growth Factor beta; Translations; Work; X-Ray Computed Tomography; airway epithelium; airway obstruction; airway remodeling; asthmatic; asthmatic patient; base; comorbidity; high risk; improved; in vivo; migration; novel; novel therapeutics; obese patients; obesity treatment; oxidant stress; post intervention; pre-clinical; rapid testing; response; single-cell RNA sequencing; specific biomarkers; therapy development; treatment response; ventilation

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.

抽象的 肥胖症是一种主要合并症和潜在的哮喘调节剂，在美国几乎影响了近40％的哮喘患者， 并增加了其严重性。肥胖哮喘患者对常规抗炎疗法没有反应 与瘦肉相比，靶向哮喘的新生物制剂在肥胖哮喘中的有效性较低。很少的研究 已经在肥胖的动物或肥胖的哮喘患者中进行，导致了主要的知识赤字。 哮喘的一个关键特征是气道重塑和纤维化，广泛定义为分布的变化， 相对于健康的患者气道壁的厚度，组成，质量或体积 患者。由于胸壁机械变化，气道重塑很难诊断 合规性可以有助于所见的身体变化。经典，气道重塑的证据和 纤维化被揭示为固定的气道异议。然而，精神法不仅对 呼吸道重塑发生的外围气道，但从根本上是无法定位的地点 重塑和纤维化。这是对气道重塑和纤维化研究的关键研究限制 哮喘正在定义疾病活动的区域，以探索疾病特异性机制。了解自然 肥胖哮喘中的气道重塑和纤维化以及快速筛查新疗法需要翻译 在临床前模型和患者之间，同时使用高级成像。使用3D的哮喘最近工作 具有129XE MRI的功能成像揭示了可逆通气缺陷的位置 （根据支气管扩张剂的响应性定义）。几项研究表明，固定缺陷代表 气道重塑和纤维化，但迄今为止，这是通过痰分析和CT扫描间接推断出来的。 我们的中心假设是，129xemri的异常通风部位代表气道重塑的区域 和纤维化，并富含具有侵入性，增殖和纤维化的成纤维细胞。我们进一步 假设氧化应力的区域改变推动了转化生长因子-beta的产生 （TGF-β）直接促启动成纤维细胞功能。最后，我们假设129xemri将是一个敏感的 肥胖的哮喘和大鼠模型的气道重塑和纤维化的特定生物标志物。经过 利用我们在临床哮喘，支气管镜检查和细胞功能/信号传导方面的专业知识方面的卓越表现 和3D MR成像在患者和动物模型中，我们都将进行离体特异性机械的 研究和体内动物模型研究通过 以下特定目的：目标1）确定病理，结构细胞谱（气道成纤维细胞和上皮 单元格）和氧化还原状态，对应于固定和可逆后置换剂缺陷（BD）的区域区域 在肥胖的哮喘患者中； 2）定义氧化还原介导的TGF-β信号的细胞需求 上皮细胞和成纤维细胞驱动肥胖哮喘中的区域重塑； 3）开发非侵入性3D成像 评估肥胖哮喘实验啮齿动物模型中气道区域重塑的技术。