Airway inflammation is a principal feature of asthma that contributes to bronchial hyperresponsiveness and disease chronicity. There is also emerging evidence that airway remodeling is a critical factor in the persistence and severity of asthma. Airway remodeling in asthma is associated with increased bronchial smooth muscle mass, mucus gland hypertrophy, angiogenesis, subepithelial fibrosis and deposition of extracellular matrix proteins. Although mechanisms for these structural changes have not been established, allergic inflammation likely contributes to this process by (1) increased local generation and deposition of extracellular matrix proteins in the airway mucosa, (2) generation of fibrogenic cytokines and (3) enhanced release of matrix metalloproteinases. Based upon current information and our own preliminary data, we hypothesize that the airway response to allergen initiates the remodeling process by (a) recruiting and activating airway inflammatory cells (eosinophils and T cells) to produce fibrogenic cytokines that, in turn, stimulate fibroblast proliferation and synthesis of fibronectin and (b) activating fibroblasts to release cytokines, chemokines and fibronectin, that, in turn, promote eosinophilic inflammation in the airway. The inflammatory and remodeling changes that follow acute allergen exposure are regulated by anti-inflammatory and antifibrotic factors, thus structural changes with persistent airflow obstruction do not typically occur in this setting. However, chronic or recurrent antigen exposure or abnormalities in antifibrotic function may lead to more permanent structural changes. This study will first establish the role of allergen in the development of cellular inflammation and initiation of airway remodeling. Proposed experiments will define the cellular recruitment and generation of inflammatory and fibrogenic cytokines, activation and proliferation of fibroblasts, as well as production and deposition of extracellular matrix proteins. Second, we will establish the relationship between the acute inflammatory response to allergen and resulting structural remodeling of the airway by defining the mechanism(s) by which (a) airway inflammatory cells (eosinophils and T cells) stimulate fibroblast proliferation and synthesis of fibronectin, and (b) fibroblasts, in turn, promote eosinophil inflammation and fibrosis in the airway. Finally, we will establish the mechanisms of enhanced airway fibrosis in asthma by investigating the intrinsic or acquired abnormalities in regulation of fibroblast function in asthma, with a specific focus on responsiveness to IFN-gamma and TGFbeta, and the influence of antigen on these abnormalities. These studies will provide new insight into the mechanisms by which allergen not only can cause airway inflammation but may also initiate structural changes in the airway (i.e. remodeling) that, under certain conditions, may lead to worsening airflow obstruction and increased disease severity.
