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.

摘要 肥胖是一种主要的合并症，也是哮喘的潜在调节剂，在美国影响着近40%的哮喘患者， 并增加其严重性。肥胖型哮喘患者对传统的抗炎治疗反应不佳 针对哮喘的新生物制剂在肥胖哮喘患者中的疗效低于瘦型哮喘患者。研究很少 已经在肥胖动物或肥胖哮喘患者中进行，导致了重大的知识缺陷。 哮喘的一个关键特征是气道重塑和纤维化，广义上定义为分布的变化， 患者气道壁的结构成分相对于健康人的厚度、组成、质量或体积 患者肥胖患者的气道重塑作为胸壁的机械性改变而难以诊断 顺应性可促成所见的生理变化。一般来说，气道重塑的证据和 肺功能测定显示纤维化为固定的气道阻塞。然而，肺量测定法不仅对肺功能不敏感， 外周气道，其中发生气道重塑，但基本上不能定位的网站， 重塑和纤维化。因此，在气道重塑和纤维化的研究中，一个关键的研究限制是， 哮喘定义疾病活动区域以探索疾病特异性机制。去了解自然 肥胖性哮喘气道重塑和纤维化的研究以及快速筛选新的治疗方法需要翻译 在临床前模型和患者之间，同时使用先进的成像技术。最近的哮喘研究使用3D 129 MRI的功能成像显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）。几项研究表明，固定缺陷代表了 气道重塑和纤维化，但迄今为止，这已经间接地从痰分析和CT扫描推断。 我们的中心假设是129 XeMRI上异常通气的部位代表气道重塑的区域 和纤维化，并且富含侵袭性、增殖性和纤维化的成纤维细胞。我们进一步 假设氧化应激的区域性改变驱动转化生长因子β的产生 (TGF-β）直接促重塑成纤维细胞功能。最后，我们假设129 XeMRI将是一种敏感的， 肥胖哮喘患者和肥胖哮喘大鼠模型气道重塑和纤维化特异性生物标志物。通过 利用我们在临床哮喘、支气管镜检查和细胞功能/信号传导方面的专业知识 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，以揭示分子和细胞功能的机制， 以下具体目的：目的1）鉴定病理学、结构细胞概况（气道成纤维细胞和上皮细胞 细胞）和对应于固定和可逆性支气管扩张剂后缺损（BD）的局部区域的氧化还原状态 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性哮喘的区域重塑; 3）开发非侵入性3D成像 技术来评估实验性肥胖哮喘啮齿动物模型中的气道局部重塑。