The role of matrix metalloproteinases (MMPs) in the pathophysiology of chronic obstructive pulmonary disease (COPD): a therapeutic role for inhibitors of MMPs?

Chronic obstructive pulmonary disease (COPD) is the collective term describing two separate chronic lung disease diseases: emphysema and chronic bronchitis (1). Initial clinical symptoms are shortness of breath and occasional cough. As the disease progresses difficulties in breathing becomes more pronounced, the cough more persistent and becomes associated with production of a clear sputum. In severe cases there are additional heart complications. The major risk factor for COPD is cigarette smoking. Between 1980 and 1990 there was a 22% increase in the occurrence of the disease with attributed 84,000 deaths in 1990 in the USA (www.nhlbi.nih.gov/health). Current therapies address the symptoms and range from bronchodilators, corticosteroids to oxygen. While there are no effective cures, although the disease can be prevented and progress slowed in many cases by removing the principal risk factor: cigarette smoking. Progression of the disease is associated with degradation of elastin in the walls of the alveoli, resulting in the functional destruction of the these organs. The net increase in proteolytic activity leading to this loss of alveoli function is a growing focus of pharmaceutical efforts for identification of a therapy for the amelioration of this disease. Of specific interest for this review has been the potential roles of members of the MMP family in both the destruction of elastin and the aberrant remodeling of damaged alveoli. An example of such a MMP is Metalloelastase. Metalloelastase (MMP-12) is (as the name suggests) capable of degrading elastin, as well as other extra-cellular matrix components. It is produced predominantly by infiltrating macrophages and appears essential for macrophage migration through extra-cellular matrix (2). Mouse metalloelastase knock-out studies implicate this enzyme as a key mediator in the pathology associated with cigarette smoke induced emhysema (3). There is also associative evidence from human genetic and animal studies suggesting a pathological link with other MMPs, such as MMPs 1,2,3,8 & 9. The evidence for the role of these MMPs in the pathological processes associated with COPD and prospects for MMP inhibitors as the basis for future therapies will be addressed in this review.