Effects of Asthma Combination Therapy on Extracellular Matrix Remodeling in Human Lung Fibroblasts

University dissertation from Lung Biology

Abstract: Fibroblasts, being one of the resident and structural cells of the lung, have the capacity to produce inflammatory mediators, cytokines and extracellular matrix (ECM) proteins perpetuating the inflammation in the airways of asthmatics. Airway remodeling is also a prominent feature of asthma that affects the lung function causing a thickening of the airways. An increased ECM production of proteoglycans, collagens and other ECM molecules, usually accompanied by dysfunction of the ECM degrading enzymes, the metalloproteinases, may not only contribute to a subepithelial fibrosis formation, but it may also be a compartment where accumulating ECM sequesters and stores inflammatory mediators. Lung fibroblasts are the major producers of ECM components within the lung and may initiate, regulate and contribute to the airway remodeling in asthma. Current asthma treatments based on anti-inflammatory glucocorticoids (GC) and bronchodilatory long acting β2-agonists (LABA) are known to improve lung function, especially when administered in combination. Airway remodeling is relatively resistant to treatment with GC, but may respond better if treated with a combination of GC and LABA. The results from this thesis, suggest that indeed, combination of GC and LABA, via complementary and additive actions, has greater potential than GC monotherapy to counteract progression of airway remodeling. By reducing the levels of the major ECM components such as proteoglycans and collagen I, treatment with combination therapy may resolve an accumulating ECM and re-establish normal ECM deposition in asthmatics.