Advanced

Budesonide/formoterol effects on metalloproteolytic balance in TGF beta-activated human lung fibroblasts

Todorova, Lizbet LU ; Gürcan, Eylem LU ; Westergren-Thorsson, Gunilla LU and Miller-Larsson, Anna (2009) In Respiratory Medicine 103(11). p.1755-1763
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Formoterol, Proteoglycans, Budesonide, TGF beta 1, Metalloproteinases, TIMP-1
in
Respiratory Medicine
volume
103
issue
11
pages
1755 - 1763
publisher
Elsevier
external identifiers
  • wos:000271156500022
  • pmid:19375904
  • scopus:70349515977
ISSN
1532-3064
DOI
10.1016/j.rmed.2009.03.018
language
English
LU publication?
yes
id
0b30c3c3-be9d-4e4a-bd10-ffb733d9b213 (old id 1505295)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19375904?dopt=Abstract
date added to LUP
2009-11-24 13:43:24
date last changed
2017-01-01 04:56:47
@article{0b30c3c3-be9d-4e4a-bd10-ffb733d9b213,
  abstract     = {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.},
  author       = {Todorova, Lizbet and Gürcan, Eylem and Westergren-Thorsson, Gunilla and Miller-Larsson, Anna},
  issn         = {1532-3064},
  keyword      = {Formoterol,Proteoglycans,Budesonide,TGF beta 1,Metalloproteinases,TIMP-1},
  language     = {eng},
  number       = {11},
  pages        = {1755--1763},
  publisher    = {Elsevier},
  series       = {Respiratory Medicine},
  title        = {Budesonide/formoterol effects on metalloproteolytic balance in TGF beta-activated human lung fibroblasts},
  url          = {http://dx.doi.org/10.1016/j.rmed.2009.03.018},
  volume       = {103},
  year         = {2009},
}