Linking Biological, Optical, and Mechanical Properties in the Airway Mucosa

连接气道粘膜的生物、光学和机械特性

• 批准号: 7736322
• 负责人: Steven CARL George
• 金额: $ 40.69万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736322
• 关键词: Acute; Acute Disease; Address; Adult Respiratory Distress Syndrome; Alveolar; Area; Asthma; Biochemical; Biological; Breathing; Cells; Chemicals; Chronic; Chronic Disease; Collagen; Collagen Fiber; Connective Tissue; Cornea; Development; Diagnosis; Diagnostic; Diffuse; Disease; Embryonic Development; Epithelial; Epithelium; Event; Extracellular Matrix; Fibrosis; Frequencies; Gel; Grant; Growth; Human; Hyperplasia; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-13; Intubation; Lamina Propria; Laser Scanning Microscopy; Lead; Link; Lung; Mechanical Stress; Mechanics; Mediator of activation protein; Mesenchymal; Methods; Microscopic; Modeling; Mucous Membrane; Mucous body substance; Nature; Obstruction; Optical Coherence Tomography; Optics; Oryctolagus cuniculus; Peripheral; Pneumonia; Population; Property; Research Design; Resolution; Respiratory physiology; Role; Severity of illness; Signal Pathway; Signal Transduction; Site; Skin; Smooth Muscle; Source; Staging; Structure; Structure of parenchyma of lung; Submucosa; Symptoms; Techniques; Tensile Strength; Testing; Time; Tissue Engineering; Tissues; Toxic Environmental Substances; Transforming Growth Factors; United States; Vascular System; Wound Healing; airway epithelium; airway remodeling; bronchial epithelium; crosslink; drug discovery; improved; in vivo; in vivo Model; injured airway; insight; minimally invasive; muscle form; novel; outcome forecast; protein expression; public health relevance; repaired; response

DESCRIPTION (provided by applicant): Airway epithelial injury occurs following inhalation of toxic agents, infection, intubation, and in a chronic repetitive disease such as asthma which impacts approximately 10% of the population in the United States. The wound repair response of the epithelium can induce changes in the structure and mechanical properties of the underlying connective tissue that can alter normal lung function. In bronchial asthma, alterations in the airway mucosa become more prominent as the disease progresses, and are correlated with disease severity, symptoms, and lung function (i.e., fixed airflow obstruction). The bronchial epithelium is known to modulate the development of the lung parenchyma during embryogenesis and these signaling pathways are likely "re- awakened" during chronic inflammatory diseases such as asthma resulting in pathological tissue growth. Our central hypothesis is that the wounded and inflamed epithelium secretes soluble mediators which diffuse into the underlying stroma at biologically active concentrations to significantly influence the mechanical properties of the matrix. Our specific aims are structured to specifically address the role of the epithelium in modulating the mechanical and optical properties of the subepithelial matrix: 1) utilizing both physical (compressive and scrape) and chemical (IL-13) injuries to the normal human bronchial epithelium in vitro, characterize the resulting impact on the optical and mechanical properties of the subepithelial matrix; 2) characterize the relationship between optical endpoints and the mechanical properties of both acellular and cellularized collagen gels in which collagen content, microstructure, and transforming growth factor-2 are systematically altered; 3) quantify changes in the optical and mechanical properties of the tracheal mucosa in a rabbit model of repeated airway epithelial injury. The proposal combines novel tissue engineering techniques which mimic the anatomical arrangement of the epithelium and lamina propria, conventional biological techniques to assess protein expression, non-traditional minimally-invasive optical techniques (multiphoton laser scanning microscopy and optical coherence tomography) to assess bulk and microscopic changes in the matrix, and an in vivo model of tracheal epithelial injury. Completion of these aims will provide insight into the underlying mechanisms of airway remodeling, and provide a platform for non-invasive diagnostics for not only the airway, but other epithelial tissues subject to chronic or acute injury (e.g., cornea, skin). PUBLIC HEALTH RELEVANCE: Airway injury, manifested primarily by asthma, is one of the most prevalent chronic diseases in the United States. Diagnosis and management remain challenging due to the chronic repetitive nature of the disease that leads to tissue remodeling. The proposal seeks to understand the link between the biological mechanisms that trigger changes in the mechanical and optical properties in the airway mucosa. The results should provide a platform for drug discovery and non-invasive diagnostics.

描述（由申请人提供）：气道上皮损伤发生在吸入有毒物质、感染、插管和慢性重复性疾病（如哮喘）后，哮喘影响美国约10%的人口。上皮细胞的伤口修复反应可以诱导基础结缔组织的结构和力学特性的改变，从而改变正常的肺功能。在支气管哮喘中，气道黏膜的改变随着疾病的进展而变得更加突出，并与疾病严重程度、症状和肺功能（即固定气流阻塞）相关。已知支气管上皮在胚胎发生期间调节肺实质的发育，这些信号通路可能在慢性炎症性疾病（如哮喘）导致病理组织生长时被“重新唤醒”。我们的中心假设是，受伤和发炎的上皮分泌可溶性介质，这些介质以生物活性浓度扩散到底层基质中，显著影响基质的机械特性。我们的具体目标是专门解决上皮在调节上皮下基质的机械和光学特性中的作用：1)利用体外正常人支气管上皮的物理（压缩和刮伤）和化学（IL-13）损伤，表征对上皮下基质光学和机械特性的影响；2)表征光学端点与脱细胞和细胞化胶原凝胶力学性能之间的关系，其中胶原含量、微观结构和转化生长因子-2被系统地改变；3)量化兔气道上皮重复损伤模型中气管粘膜光学和力学性能的变化。该提案结合了模仿上皮和固有层解剖排列的新型组织工程技术、评估蛋白质表达的传统生物技术、评估基质的体积和微观变化的非传统微创光学技术（多光子激光扫描显微镜和光学相干断层扫描）以及气管上皮损伤的体内模型。完成这些目标将有助于深入了解气道重塑的潜在机制，并为气道，以及其他慢性或急性损伤上皮组织（如角膜，皮肤）的非侵入性诊断提供平台。公共卫生相关性：气道损伤，主要表现为哮喘，是美国最常见的慢性疾病之一。诊断和管理仍然具有挑战性，由于慢性重复性疾病的性质，导致组织重塑。该提案旨在了解触发气道粘膜机械和光学特性变化的生物学机制之间的联系。研究结果将为药物发现和非侵入性诊断提供一个平台。