Extracellular Matrix Synthesis and Turnover in Asthma

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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.