Extracellular Matrix Synthesis and Turnover in Asthma

描述（由申请人提供）：组织的细胞结构是由细胞外基质（ECM）组织的，这种组织是正常器官功能所必需的。细胞外基质（ECM）的改变在哮喘患者的气道中起重要作用。然而，特定基质成分的作用、它们的作用机制以及这些变化与哮喘的关系仍然知之甚少。ECM曾经被认为是惰性支架，在支持和维持组织结构方面只有机械作用。然而，ECM已经被证明可以影响炎症细胞的分布、激活状态和存活，以及炎症细胞的粘附，并可以作为炎症介质和生长因子的储存库。慢性炎症诱导的ECM组织可能导致气道结构和功能的改变，这一过程在人类中被称为重塑。这与哮喘气道特别相关，其中ECM蛋白的谱被改变。透明质酸（HA）是ECM的重要组成部分，通常在成人组织中少量发现，但在伤口愈合过程中含量较高。哮喘患者支气管肺泡灌洗液（BALF）中的HA水平升高，其水平与疾病的严重程度相关。基于我们的初步数据，我们假设透明质酸的合成及其与l- α -l和TSG-6的相互作用对于指导炎症肺中白细胞的保留和定位的基质组织是必要的，慢性炎症导致过量的基质沉积和随后气道结构和功能的改变。为了验证这一假设，我们将执行以下具体目标。具体目标1：确定TSG-6和l- α - 1在小鼠过敏原刺激模型中的作用。特异性目的2：确定血凝素基质在肺炎症细胞募集中的作用。特异性目的3：确定慢性间断性抗原暴露对基质合成和周转的作用，确定这些变化在抗原退出后是可逆的还是固定的，并确定对气道结构和功能的影响。

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.