Budesonide/formoterol effects on metalloproteolytic balance in TGFbeta-activated human lung fibroblasts.
In the airways of asthmatic patients, activated fibroblasts account for an excessive matrix production including proteoglycans (PGs). Transforming growth factor-beta (TGFbeta), metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play key roles 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 24h with TGFbeta1 (10 ng/ml) without/with budesonide (10(-9) to 10(-6)M) and/or formoterol (10(-11) to 10(-6)M). TGFbeta1 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 alone 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 TGFbeta1-induced PG production. This implies that budesonide/formoterol combination therapy can counteract excessive matrix production and thus pathological airway fibrotic remodeling in asthma.
Experimental Medical Science, Lund University, Lund, Sweden.
Lizbet
L
Todorova
Eylem
E
Gürcan
Gunilla
G
Westergren-Thorsson
Anna
A
Miller-Larsson
D001249:Asthma / Q000188:drug therapy / Q000378:metabolism*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D019819:Budesonide / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D000068759:Formoterol Fumarate; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D011509:Proteoglycans / Q000096:biosynthesis; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D001993:Bronchodilator Agents; D004983:Ethanolamines; D011509:Proteoglycans; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D019819:Budesonide; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000068759:Formoterol Fumarate