Extracellular Matrix Synthesis and Turnover in Asthma

哮喘中的细胞外基质合成和周转

• 批准号: 7659572
• 负责人: MARK A ARONICA
• 金额: $ 36.79万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659572
• 关键词: Adherence; Adhesions; Adult; Affect; Allergens; Allergic; Antigens; Architecture; Area; Asthma; Binding; Biological Assay; Bone Marrow; Bronchoalveolar Lavage Fluid; Cells; Chronic; Confocal Microscopy; Data; Deposition; Development; Extracellular Matrix; Extracellular Matrix Proteins; Genes; Growth Factor; Human; Hyaluronan; Immunohistochemistry; Inflammation; Inflammation Mediators; Inflammatory; Knockout Mice; Lead; Leukocytes; Lung; Lymphocyte; Mechanics; Modeling; Mus; Organ; Play; Positioning Attribute; Process; Production; Recovery; Research Personnel; Role; Severity of illness; Structure; Testing; Tissues; Withdrawal; Wound Healing; airway epithelium; asthmatic airway; base; cell motility; chemokine; human subject; inter-alpha-inhibitor; programs; scaffold

DESCRIPTION (provided by applicant): The cellular architecture of tissues is organized by the extracellular matrix (ECM) and this organization is required for proper organ function. Alterations in the extracellular matrix (ECM) play an important role in the airways of asthmatics. However, the role of specific matrix components, mechanisms by which they function and how these changes relate to asthma are still poorly understood. The ECM was once thought to be inert scaffolding, having only a mechanical role in supporting and maintaining tissue structure. However, ECM has been shown to influence the distribution, activation status and survival, as well as adhesion of inflammatory cells and can act as a reservoir for inflammatory mediators and growth factors. The organization of the ECM induced by chronic inflammation may lead to alterations in airway structure and function, a process that has been referred to as remodeling in humans. This is of particular relevance in the asthmatic airways, in which the profile of ECM proteins is altered. Hyaluronan (HA) is an important component of the ECM normally found in adult tissues in small amounts but is present in higher amounts during wound healing. HA levels are increased in the bronchoalveolar lavage fluid (BALF) from asthmatics, and their level is associated with the severity of disease. Based on our preliminary data, we hypothesize that synthesis of hyaluronan and its interaction with l-alpha-l and TSG-6 are necessary for the matrix organization that directs the retention and positioning of leukocytes in the inflamed lung, with chronic inflammation leading to excess matrix deposition and subsequent altered airway structure and function. To test this hypothesis we will perform the following specific aims. Specific Aim 1: Define the role of TSG-6 and l-alpha-l in a murine allergen challenge model. Specific Aim 2: Determine the role of the HA matrix in inflammatory cell recruitment to the lung. Specific Aim 3: Determine the role of chronic-intermittent antigen exposure on matrix synthesis and turnover, determine if these changes are reversible or fixed after antigen withdrawal and determine the effects on airway structure and function.

描述（由申请人提供）：组织的细胞结构由细胞外基质（ECM）组织，并且该组织是适当的器官功能所必需的。细胞外基质（ECM）的改变在哮喘患者的气道中起着重要作用。但是，特定基质组件的作用，它们起作用的机制以及这些变化如何与哮喘有关。 ECM曾经被认为是惰性的脚手架，在支持和维持组织结构中只有机械作用。但是，ECM已被证明会影响分布，激活状态和存活以及炎症细胞的粘附，并可以充当炎症介质和生长因子的储层。慢性炎症引起的ECM的组织可能导致气道结构和功能的改变，这一过程被称为人类重塑。这在哮喘气道中特别相关，其中ECM蛋白的特征被改变。透明质酸（HA）是通常在成年组织中发现的ECM的重要组成部分，但在伤口愈合过程中较高量。哮喘患者的支气管肺泡灌洗液（BALF）的HA水平升高，其水平与疾病的严重程度有关。根据我们的初步数据，我们假设透明质酸的合成及其与L-Alpha-L和TSG-6的相互作用对于指导发炎性肺中白细胞的保留和定位的基质组织是必需的，慢性炎症会导致慢性炎症，导致过量的Matrix depositix and Matrix Deposition和后续空气结构和随后的空气结构和更改的更改功能。为了检验这一假设，我们将执行以下特定目标。具体目标1：定义TSG-6和L-Alpha-L在鼠过敏原挑战模型中的作用。特定目标2：确定HA基质在肺部募集到肺中的作用。具体目标3：确定慢性年度抗原暴露在基质合成和离职率中的作用，确定这些变化是可逆的还是抗原撤离后固定的，并确定对气道结构和功能的影响。