The Role of Proteinases in Experimental Asthma

Baylor College Of Medicine, Houston TX

Investigators

Linked publications & trials

Abstract

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