Sarcoidosis is a systemic inflammatory disorder in which infiltration of macrophages and lymphocytes, together with a network of cytokines, chemokines and growth factors lead to granuloma formation. Although pulmonary sarcoidosis can undergo spontaneous remission, chronic inflammation and granulomas can cause the remodeling of lung resulting in the development of fibrosis and end organ function. Cell migration and extracellular matrix (ECM) remodeling are events in which the plasminogen (Pig) and matrix metalloproteinase (MMP) systems play a significant biological role. Recently, several studies have identified MMP-2, MMP-9 and MMP-14 in BAL fluid and granulomas of sarcoid patients. Nevertheless, although the evidence for an important relationship between Pig, MMP, inflammatory cell migration and tissue remodeling is now becoming quite extensive, the linkage of Pig and the MMP systems to granuloma formation and fibrosis in the setting of specific cytokine profiles (Th1 vs. Th2) is unknown. Our hypothesis is that Pig and the MMPs are involved in the regulation of cytokines and growth factors that influence cell recruitment, granuloma formation, lung remodeling and ultimately fibrosis, and that Pig inhibitors would be effective in the treatment of sarcoidosis. Accordingly, the overall goal of this project is to provide new insights into the fundamental mechanisms underlying the inflammatory response leading to granuloma formation and fibrosis and to identify novel targets for the treatment of sarcoidosis.
The specific aims are: 1) To elucidate the role of Pig, MMP-2, MMP-9 and MMP-14 in granuloma formation and fibrosis in transgenic mice using non-infectious granuloma models with two distinct cytokine profiles. 2) To establish the mechanism by which Pig and the MMPs contribute to granuloma formation and fibrosis. 3) To assess plasmin(ogen) as a therapeutic target for the treatment of sarcoidosis. This proposal is part of a 5 year career development plan that will include course work in immunology, genetic epidemiology and pulmonary pathology. By interacting with basic scientists and clinicians in the Department of Pulmonary, Allergy and Critical Care Medicine and the Lerner Research Institute at the Cleveland Clinic Lerner College of Medicine-CWRU, Dr. Carmen M. Swaisgood will gain unique insights and experience which will assist her in making a successful transition to an independent translational researcher in the field of pulmonary pathobiology in general and of sarcoidosis in particular.
