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 肥胖是一种主要的合并症，也是哮喘的潜在调节因素，影响着美国近 40% 的哮喘患者， 并增加其严重程度，肥胖哮喘患者对传统抗炎疗法的反应不佳。 与瘦人相比，针对哮喘的新生物制剂对肥胖哮喘患者的疗效较差。 已在肥胖动物或肥胖哮喘患者中进行，导致严重的知识缺陷。 哮喘的一个关键特征是气道重塑和纤维化，广泛定义为气道分布的变化， 患者气道壁结构成分相对于健康人的厚度、成分、质量或体积 由于胸壁的机械变化，肥胖患者的气道重塑很难诊断。 传统上，顺应性可以促成所见的生理变化，以及气道重塑的证据。 纤维化在肺活量测定中表现为固定性气道阻塞。然而，肺活量测定不仅对肺功能不敏感。 周围气道，气道重塑发生的地方，但基本上无法定位气道重塑的部位 因此，气道重塑和纤维化研究的一个关键研究局限性。 哮喘正在定义疾病活动区域以探索疾病特异性机制以了解其本质。 肥胖哮喘气道重塑和纤维化的研究以及快速筛选新疗法需要转化 临床前模型和患者之间的研究，同时使用最近使用 3D 进行哮喘研究的工作。 129Xe MRI 功能成像揭示了可逆性和固定性通气缺陷的位置 （根据支气管扩张剂反应性定义）。一些研究表明，固定缺陷代表了部位。 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 上通气异常的部位代表气道重塑区域 和纤维化，并富含具有侵袭性、增殖性和纤维化性的成纤维细胞。 发现氧化应激的区域变化驱动转化生长因子-β的产生 (TGF-β) 直接促重塑成纤维细胞功能 最后，我们追求 129XeMRI 将是一种敏感且可靠的方法。 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。 利用我们在临床哮喘、支气管镜检查和细胞功能/信号转导方面的转化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，我们将进行离体细胞特异性机制 研究和体内动物模型研究，通过以下方式揭示分子和细胞功能的机制 具体目标如下： 目标 1) 确定病理学、结构细胞概况（气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 肥胖哮喘患者；2) 定义气道之间氧化还原介导的 TGF-β 信号传导的细胞需求 上皮细胞和成纤维细胞驱动肥胖哮喘的区域重塑 3) 开发非侵入性 3D 成像 评估肥胖哮喘实验啮齿动物模型气道区域重塑的技术。