Extracellular Matrix Synthesis and Turnover in Asthma

描述（由申请人提供）：组织的细胞结构由细胞外基质（ECM）组织，该组织是正常器官功能所需的。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，它们发挥作用的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仅具有机械作用。然而，ECM已被证明影响炎性细胞的分布、活化状态和存活以及粘附，并且可以充当炎性介质和生长因子的储存库。由慢性炎症诱导的ECM的组织化可能导致气道结构和功能的改变，这一过程被称为人体重塑。这在哮喘气道中是特别相关的，其中ECM蛋白质的谱被改变。透明质酸（HA）是ECM的重要成分，通常在成人组织中以少量存在，但在伤口愈合期间以较高的量存在。哮喘患者支气管肺泡灌洗液（BALF）中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白细胞在发炎肺中的保留和定位的基质组织是必需的，慢性炎症导致过量基质沉积和随后改变的气道结构和功能。为了验证这个假设，我们将执行以下具体目标。具体目标1：确定TSG-6和1-α-l在鼠变应原激发模型中的作用。具体目标2：确定HA基质在炎症细胞向肺募集中的作用。具体目标3：确定慢性-间歇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撤除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.