This project will delineate the role of pulmonary proteolysis in the pathogenesis of asthma. The protease uPA and its inhibitor, PAI-1, have been implicated in the pathogenesis of pulmonary disorders. Little attention has been given to their potential role in asthma despite their involvement in the modulation of inflammation, activation of cytokines, and extracellular matrix turnover. We initially hypothesized that a disturbance in the balance between uPA and PAI-1 is pivotal to the airway remodeling seen in asthma. Our preliminary data have led us to further hypothesize that augmentation of pulmonary proteolysis unleashed by a decrease in PAI-1 initiates and perpetuates airway inflammation, injury, and repair. Location and temporal changes in the activity and quantity of uPA and PAI-I in the development of the asthma phenotype using mice that are transgenic over-expressors of PAI-1. We will determine whether a disturbance in uPA and PAI-1 balance is present in asthmatics by assaying induced sputum for uPA and PAI-1 amount and activity. Definition of the mechanisms that alter uPA and PAI balance, and the importance of this balance will provide support for the future development of novel therapeutic or prophylactic pharmacotherapy of asthma that targets uPA and/or PAI-1.
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