Inhaled corticosteroids decrease subepithelial collagen deposition by modulation of the balance between matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression in asthma

Background: Bronchial asthma is characterized by airway wall remodeling. Matrix metalloproteinases (MMPs) are members of a family of proteolytic enzymes that degrade the extracellular matrix and that restrain the effects of their tissue inhibitors (TIMPs). Treatment with inhaled corticosteroids may prevent airway remodeling in asthma. However, the effects of corticosteroid treatment on MMPs and TIMPs in asthma are unknown. Objective: We examined the effects of inhaled beclomethasone dipropionate (BDP) on the expression of MMP-9 and TIMP-1 and subepithelial collagen deposition in bronchial biopsy specimens from 30 subjects with asthma. Methods: Inhaled BDP, 800 mu g daily, or placebo was administered for 6 months in a double-blind, parallel-group study, and bronchial biopsies were performed before and after treatment. Biopsy specimens were examined for extent of collagen type III in the subepithelial basement membrane by means of immunohistochemistry, and expression of both epithelial and submucosal MMP-9 and TIMP-1 was quantitated. Numbers of inflammatory cells were also determined. Results: We observed significant decreases in collagen type III deposition (P < .01) and the expression of submucosal MMP-9 (P < .01) and a significant increase in the expression of submucosal TIMP-1 (P < .05) In the BDP group. Significant correlations were found between the subepithelial collagen type III deposition and epithelial (r(s) = 0.37, P < 0.5) and submucosal expression of MMP-9 (r(s) = 0.47, P < .01). Additionally, the number of many inflammatory cells and myofibroblasts in airway mucosa were significantly decreased in the BDP group. Conclusion: Our findings suggest that corticosteroid treatment of asthma can reduce subepithelial collagen deposition by downregulation of MMP-9 expression and upregulation of TIMP-1 expression.