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TGFβ-induced matrix production by bronchial fibroblasts in asthma: Budesonide and formoterol effects.

Todorova, Lizbet LU ; Bjermer, Leif LU ; Westergren-Thorsson, Gunilla LU and Miller-Larsson, Anna (2011) In Respiratory Medicine 105(9). p.1296-1307
Abstract
To investigate the mechanisms of enhanced airway deposition of subepithelial collagen in asthma and its sensitivity to drug therapy with combination of an inhaled glucocorticosteroid (GC) and a long-acting β(2)-agonist (LABA), a cell model system involving bronchial fibroblasts derived from biopsies from patients with stable mild-to-moderate asthma has been used. To mimic unstable conditions and severe asthma, fibroblasts were stimulated ex vivo with TGFβ1. Primary fibroblasts established from central bronchial biopsies from 8 asthmatic patients were incubated for 24 h with 0.4% serum or TGFβ1 (10 ng/ml) with/without the GC budesonide (BUD; 10 nM) and/or the LABA formoterol (FORM; 0.1 nM). Procollagen peptide I (PICP), metalloproteinase... (More)
To investigate the mechanisms of enhanced airway deposition of subepithelial collagen in asthma and its sensitivity to drug therapy with combination of an inhaled glucocorticosteroid (GC) and a long-acting β(2)-agonist (LABA), a cell model system involving bronchial fibroblasts derived from biopsies from patients with stable mild-to-moderate asthma has been used. To mimic unstable conditions and severe asthma, fibroblasts were stimulated ex vivo with TGFβ1. Primary fibroblasts established from central bronchial biopsies from 8 asthmatic patients were incubated for 24 h with 0.4% serum or TGFβ1 (10 ng/ml) with/without the GC budesonide (BUD; 10 nM) and/or the LABA formoterol (FORM; 0.1 nM). Procollagen peptide I (PICP), metalloproteinase (MMP)-1 and tissue inhibitor of MMPs (TIMP-1) were determined in culture media using ELISA while the activity of MMP-2, -3, -9 by zymography. Metabolically labeled proteoglycans, biglycan and decorin, associated with collagen fibrillation/deposition, were separated using chromatography and SDS-PAGE. The levels of PICP and biglycan were increased 2-fold by TGFβ1 (p < 0.05). The BUD and FORM combination reduced the PICP increase by 58% (p < 0.01) and the biglycan by 36% (p < 0.05) while each drug alone had no effect. Decorin levels were reduced by TGFβ1 in fibroblasts of most patients; BUD alone and BUD and FORM completely counteracted this decrease. MMPs and TIMP-1 were not affected by TGFβ1 or the drugs. These results suggest that BUD and FORM combination therapy, without affecting metalloproteolytic balance, has a potential to counteract enhanced collagen production by bronchial fibroblasts in asthma and to normalize the production of small proteoglycans which may affect collagen fibrillation and deposition. (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
Lung fibroblasts, Budesonide/formoterol, Asthma, Extracellular matrix, Metalloproteinases, TGF beta 1
in
Respiratory Medicine
volume
105
issue
9
pages
1296 - 1307
publisher
Elsevier
external identifiers
  • wos:000293723800006
  • pmid:21514131
  • scopus:79960448691
ISSN
1532-3064
DOI
10.1016/j.rmed.2011.03.020
language
English
LU publication?
yes
id
9a6712fe-3fc5-498a-b9dd-0e5b1979621e (old id 1936821)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21514131?dopt=Abstract
date added to LUP
2011-05-02 15:25:40
date last changed
2017-01-01 06:28:35
@article{9a6712fe-3fc5-498a-b9dd-0e5b1979621e,
  abstract     = {To investigate the mechanisms of enhanced airway deposition of subepithelial collagen in asthma and its sensitivity to drug therapy with combination of an inhaled glucocorticosteroid (GC) and a long-acting β(2)-agonist (LABA), a cell model system involving bronchial fibroblasts derived from biopsies from patients with stable mild-to-moderate asthma has been used. To mimic unstable conditions and severe asthma, fibroblasts were stimulated ex vivo with TGFβ1. Primary fibroblasts established from central bronchial biopsies from 8 asthmatic patients were incubated for 24 h with 0.4% serum or TGFβ1 (10 ng/ml) with/without the GC budesonide (BUD; 10 nM) and/or the LABA formoterol (FORM; 0.1 nM). Procollagen peptide I (PICP), metalloproteinase (MMP)-1 and tissue inhibitor of MMPs (TIMP-1) were determined in culture media using ELISA while the activity of MMP-2, -3, -9 by zymography. Metabolically labeled proteoglycans, biglycan and decorin, associated with collagen fibrillation/deposition, were separated using chromatography and SDS-PAGE. The levels of PICP and biglycan were increased 2-fold by TGFβ1 (p &lt; 0.05). The BUD and FORM combination reduced the PICP increase by 58% (p &lt; 0.01) and the biglycan by 36% (p &lt; 0.05) while each drug alone had no effect. Decorin levels were reduced by TGFβ1 in fibroblasts of most patients; BUD alone and BUD and FORM completely counteracted this decrease. MMPs and TIMP-1 were not affected by TGFβ1 or the drugs. These results suggest that BUD and FORM combination therapy, without affecting metalloproteolytic balance, has a potential to counteract enhanced collagen production by bronchial fibroblasts in asthma and to normalize the production of small proteoglycans which may affect collagen fibrillation and deposition.},
  author       = {Todorova, Lizbet and Bjermer, Leif and Westergren-Thorsson, Gunilla and Miller-Larsson, Anna},
  issn         = {1532-3064},
  keyword      = {Lung fibroblasts,Budesonide/formoterol,Asthma,Extracellular matrix,Metalloproteinases,TGF beta 1},
  language     = {eng},
  number       = {9},
  pages        = {1296--1307},
  publisher    = {Elsevier},
  series       = {Respiratory Medicine},
  title        = {TGFβ-induced matrix production by bronchial fibroblasts in asthma: Budesonide and formoterol effects.},
  url          = {http://dx.doi.org/10.1016/j.rmed.2011.03.020},
  volume       = {105},
  year         = {2011},
}