Episodic dyspnea, lung inflammation, and in some patients, progressive irreversible airway dysfunction characterizes asthma. Proteases influence asthma: inhibition of proteases abrogates acute airway hyperresponsiveness (AHR) and alters T cell effector development, respectively. This proposal will define the role of proteases in an acute asthma model and extend these observations to develop a chronic model of asthma that more closely mimics the airway remodeling seen in human disease. Further understanding of the role of proteases and the mechanism of reactive stroma formation potentially offers new opportunities at therapeutic intervention. Specifically, the first aim will determine spatio-temporal regulation of proteases synthesized in the lung of mice exhibiting the asthma phenotype. Serine proteases and MMPs are upregulated in the bronchoalveolar lavage and lung parenchyma of antigen challenged mice. We hypothesize a reciprocal relationship in which endogenous protease expression is essential for efficient Th2 cell development and recruitment and Th2 cells in turn determine airway protease expression.
The second aim will determine the role of endogenous proteases in the progression of reactive stroma. Expression of proteases and airway inflammation, independent of the acute asthma phenotype, elicits reactive stroma formation, collagen deposition, and airway remodeling. We hypothesize that dysregulated airway protease activity modifies the chronic asthma phenotype by accelerating, or preventing resolution of, airway matrix remodeling. Airway collagen synthesis, AHR, and goblet cell metaplasia in mice chronically challenged with antigen and protease inhibitors will be determined. Finally, our third aim will determine the role of exogenous proteases in modifying the host response to the allergen in the experimental model of asthma Antigens implicated in human asthma have intrinsic protease activity. We have recently shown that proteases present in the antigen derived from Aspergillus fumigatus significantly modify T cell effector development in vivo. We hypothesize that these proteases critically influence development of the acute asthma phenotype. We propose that these proteases modify airway matrix remodeling, either by acting directly on airway matrix or by degrading host inhibitors of endogenous enzymes. Insight into this area of allergic inflammation will answer important questions on mechanisms of acute and chronic airway disease. This work may serve as the foundation for future therapeutic studies that target a broad range of asthmatic patients.
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