In the airways of asthmatic patients, activated fibroblasts account for an excessive matrix production including proteoglycans (PGs). Transforming growth factor-beta. (TGF beta), metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play key rotes in matrix turnover. It is unclear whether asthma therapy with combination of inhaled glucocorticoids and long-acting beta(2)-agonists affects metalloproteolytic equilibrium and by that counteracts airway fibrosis. The effects of the glucocorticoid, budesonide, and the long-acting beta(2)-agonist, formoterol, on the PG production and the activity of PGs' main regulators: MMP-3, MMP-9, MMP-2 and TIMP-1 were investigated in human lung fibroblasts (HFL-1) treated for 24 h with TGF beta 1 (10 ng/ml) without/with budesonide (10(-9) to 10(-6) M) and/or formoterol (10(-11) to 10(-6) M). TGF beta 1 significantly increased production of PGs and TIMP-1, and the activity of MMP-3, MMP-9 and MMP-2. Concurrent budesonide/formoterol combination counteracted the enhanced: PG and TIMP-1 production, MMP-9 activity and MMP-9/TIMP-1 ratio, whereas MMP-2 and MMP-3 were not affected and so their ratios to TIMP-1 were significantly increased. Budesonide or formoterol. alone achieved equal effects as budesonide/formoterol on MMP-9 and MMP-9/TIMP-1 ratio but had no effects on TIMP-1, MMP-2 or MMP-3. In the formoterol. absence, higher budesonide concentrations were required to reduce the PG production, whereas formoterol atone had no effects. These results suggest that the budesonide/formoterol combination enhanced metalloproteolytic activity of human lung fibroblasts via a synergistic decrease of TIMP-1, and that this mechanism may be involved in the synergistic inhibition of the TGF beta 1-induced PG production. This implies that budesonide/formoterol combination therapy can counteract excessive matrix production and thus pathological airway fibrotic remodeling in asthma. (C) 2009 Elsevier Ltd. All rights reserved.
Subject classification (UKÄ)
- Respiratory Medicine and Allergy
- TGF beta 1