The Role of Proteinases in Experimental Asthma

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Over the last several decades allergic asthma and related atopic syndromes have emerged as major public health concerns. Studies from around the world suggest that the incidence and prevalence of asthma began to rise more than two decades ago with no signs that these disturbing trends may be reversing. Asthma is characterized by episodic dyspnea, lung inflammation, and in some patients, progressive irreversible airway dysfunction. Experimental models that share many features in common with human asthma have shed much light on underlying pathologic mechanisms. The central question addressed in this proposal relates to our discovery that proteinases play distinct roles in development and resolution of allergic airway inflammation. In particular, the acute phase of allergic inflammation in the lung is accompanied by increased local proteolytic activity, which we found plays a key role in progression of experimental asthma. We have shown that several members of the matrix metalloproteinase (MMP) family show a regulated expression in the lungs of mice that exhibit the asthma phenotype and that this upregulation is part of the crosstalk between the cytokines released by the inflammatory cell, and certain types of resident lung parenchymal cells. Further, we show that neither the expression nor biological activity of MMPs is required for the development of Th2 cells in response to allergen challenge. Nonetheless, the importance of upregulation of MMPs in allergic lung disease is underscored by our recent reports showing that mice deficient in MMP2, MMP9 or both show enhanced accumulation of lung inflammatory cells and are susceptible to asphyxiation when exposed to allergens. Using an acute and chronic model of asthma, the overall aim of this proposal is to define the role of key MMPs and syndecan-1, an epithelial proteoglycan in coordinating the crosstalk between immune and non-immune cells in the lung and in orchestrating the progression of allergic inflammation and clearance of inflammatory cells from lung. The significance of our studies includes providing insight into the basic mechanism behind progression of allergic lung inflammation and determining novel molecules that can potentially improve clearance of airway inflammation. Together these findings will substantially contribute to the understanding of regulation of Th2 immunity and will provide new approaches for the treatment of asthma.