Understanding the role of matrix metalloproteinases in tissue destruction during disease processes
Columbia University, College of Physicians & Surgeons
630 W. 168th Street, P&S 9-449
New York, NY, 10032
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The research in our laboratory centers on several projects directed at understanding the role of matrix metalloproteinases in tissue destruction during disease processes. Our laboratory has made use of transgenic mice in which to express these enzymes at pathophysiological levels in specific tissues so as to recreate the natural proteolytic imbalance. Through the generation of these transgenic animals we have been able to develop several mouse models of emphysema, atherosclerosis and heart failure and also gain insight into the role these enzymes may be playing in the pathogenesis of these diseases.
Several years ago we demonstrated that transgenic mice which express human MMP-1 (matrix metalloproteinase 1, interstitial collagenase) in the lung develop emphysema. We have recently demonstrated that human patients with emphysema express MMP-1 within their lung parenchyma and normal patients do not. In this study it was found that the type II pneumocyte of the lung of patients with emphysema expressed MMP-1. Therefore, we are proceeding with in vitro studies to determine the mechanism by which MMP-1 is induced in the type II pneumocyte. In our preliminary work we have found that cigarette smoke extract can induce MMP-1 expression in lung epithelial cells and this occurs through activation of the MAP Kinase signaling pathway. Through in vitro promoter studies we have identified the region of the MMP-1 promoter that responds to cigarette smoke.
These studies demonstrate that cigarette smoke induced changes on the epithelial cell of the lung from patients with emphysema may be critical in disease pathogenesis. Our future studies will attempt to identify the molecular pathway leading to up regulation of MMP-1 and other genes in the emphysema lung and possibly provide us with alternative drug targets for this disease.
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