Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation

Qiuhong Fang, Nancy A. Schulte, Huijung Kim, Tetsu Kobayashi, Xingqi Wang, Anna Miller-Larsson, Elisabet Wieslander, Myron Lee Toews, Xiang-de Liu, Stephen I. Rennard

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: The balance between production and degradation of extracellular matrix is crucial in maintaining normal tissue structure. This study was designed to investigate the effect of budesonide on fibroblast-mediated tissue repair and remodeling. Methods: Using human fetal lung fibroblasts in a three-dimensional collagen gel culture system, we investigated the effect of budesonide (1-1000 nM) on collagen gel contraction and degradation in the presence or absence of inflammatory cytokines (interleukin-1β and tumor necrosis factor α 5 ng/mL each) and, in order to activate latent proteases, serine protease trypsin 0.25 μg/mL. The effects of budesonide on metalloproteinase production and activation were also investigated. Results: Inflammatory cytokines significantly inhibited collagen gel contraction mediated by lung fibroblasts. Budesonide counteracted the effect of cytokines in a concentration-dependent manner (to 50%, P < 0.01). Budesonide 100 nM almost completely inhibited the release and mRNA expression of metalloproteinase-1, metalloproteinase-3, and metalloproteinase-9 induced by the cytokines (P < 0.05). Exposure to the cytokines plus trypsin increased collagen degradation and conversion of the metalloproteinases to lower molecular weight forms corresponding to their active forms. Budesonide blocked both enhanced collagen degradation (P < 0.01) and suppressed trypsin-mediated conversion of cytokine-induced metalloproteinase-9 and metalloproteinase-3 to lower molecular weight forms. Similar effects were observed with dexamethasone 1 μM, suggesting a class effect. Conclusion: These findings demonstrate that budesonide directly modulates contraction of collagen gels and can decrease collagen degradation under inflammatory conditions. The mechanism of this effect is through suppressing gene expression, release, and activation of metalloproteinases. By modulating the release and activity of metalloproteinases, inhaled budesonide may be able to modify airway tissue repair and remodeling.

Original languageEnglish (US)
Pages (from-to)25-33
Number of pages9
JournalJournal of Inflammation Research
Volume6
Issue number1
DOIs
StatePublished - Feb 26 2013

Fingerprint

Budesonide
Metalloproteases
Collagen
Fibroblasts
Gels
Cytokines
Trypsin
Molecular Weight
Lung
Serine Proteases
Interleukin-1
Dexamethasone
Transcriptional Activation
Extracellular Matrix
Peptide Hydrolases
Tumor Necrosis Factor-alpha
Gene Expression
Messenger RNA

Keywords

  • Budesonide
  • Metalloproteinase
  • Tissue remodeling

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Fang, Q., Schulte, N. A., Kim, H., Kobayashi, T., Wang, X., Miller-Larsson, A., ... Rennard, S. I. (2013). Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation. Journal of Inflammation Research, 6(1), 25-33. https://doi.org/10.2147/JIR.S35136

Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation. / Fang, Qiuhong; Schulte, Nancy A.; Kim, Huijung; Kobayashi, Tetsu; Wang, Xingqi; Miller-Larsson, Anna; Wieslander, Elisabet; Toews, Myron Lee; Liu, Xiang-de; Rennard, Stephen I.

In: Journal of Inflammation Research, Vol. 6, No. 1, 26.02.2013, p. 25-33.

Research output: Contribution to journalArticle

Fang, Q, Schulte, NA, Kim, H, Kobayashi, T, Wang, X, Miller-Larsson, A, Wieslander, E, Toews, ML, Liu, X & Rennard, SI 2013, 'Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation', Journal of Inflammation Research, vol. 6, no. 1, pp. 25-33. https://doi.org/10.2147/JIR.S35136
Fang Q, Schulte NA, Kim H, Kobayashi T, Wang X, Miller-Larsson A et al. Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation. Journal of Inflammation Research. 2013 Feb 26;6(1):25-33. https://doi.org/10.2147/JIR.S35136
Fang, Qiuhong ; Schulte, Nancy A. ; Kim, Huijung ; Kobayashi, Tetsu ; Wang, Xingqi ; Miller-Larsson, Anna ; Wieslander, Elisabet ; Toews, Myron Lee ; Liu, Xiang-de ; Rennard, Stephen I. / Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation. In: Journal of Inflammation Research. 2013 ; Vol. 6, No. 1. pp. 25-33.
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abstract = "Background: The balance between production and degradation of extracellular matrix is crucial in maintaining normal tissue structure. This study was designed to investigate the effect of budesonide on fibroblast-mediated tissue repair and remodeling. Methods: Using human fetal lung fibroblasts in a three-dimensional collagen gel culture system, we investigated the effect of budesonide (1-1000 nM) on collagen gel contraction and degradation in the presence or absence of inflammatory cytokines (interleukin-1β and tumor necrosis factor α 5 ng/mL each) and, in order to activate latent proteases, serine protease trypsin 0.25 μg/mL. The effects of budesonide on metalloproteinase production and activation were also investigated. Results: Inflammatory cytokines significantly inhibited collagen gel contraction mediated by lung fibroblasts. Budesonide counteracted the effect of cytokines in a concentration-dependent manner (to 50{\%}, P < 0.01). Budesonide 100 nM almost completely inhibited the release and mRNA expression of metalloproteinase-1, metalloproteinase-3, and metalloproteinase-9 induced by the cytokines (P < 0.05). Exposure to the cytokines plus trypsin increased collagen degradation and conversion of the metalloproteinases to lower molecular weight forms corresponding to their active forms. Budesonide blocked both enhanced collagen degradation (P < 0.01) and suppressed trypsin-mediated conversion of cytokine-induced metalloproteinase-9 and metalloproteinase-3 to lower molecular weight forms. Similar effects were observed with dexamethasone 1 μM, suggesting a class effect. Conclusion: These findings demonstrate that budesonide directly modulates contraction of collagen gels and can decrease collagen degradation under inflammatory conditions. The mechanism of this effect is through suppressing gene expression, release, and activation of metalloproteinases. By modulating the release and activity of metalloproteinases, inhaled budesonide may be able to modify airway tissue repair and remodeling.",
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AU - Miller-Larsson, Anna

AU - Wieslander, Elisabet

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AB - Background: The balance between production and degradation of extracellular matrix is crucial in maintaining normal tissue structure. This study was designed to investigate the effect of budesonide on fibroblast-mediated tissue repair and remodeling. Methods: Using human fetal lung fibroblasts in a three-dimensional collagen gel culture system, we investigated the effect of budesonide (1-1000 nM) on collagen gel contraction and degradation in the presence or absence of inflammatory cytokines (interleukin-1β and tumor necrosis factor α 5 ng/mL each) and, in order to activate latent proteases, serine protease trypsin 0.25 μg/mL. The effects of budesonide on metalloproteinase production and activation were also investigated. Results: Inflammatory cytokines significantly inhibited collagen gel contraction mediated by lung fibroblasts. Budesonide counteracted the effect of cytokines in a concentration-dependent manner (to 50%, P < 0.01). Budesonide 100 nM almost completely inhibited the release and mRNA expression of metalloproteinase-1, metalloproteinase-3, and metalloproteinase-9 induced by the cytokines (P < 0.05). Exposure to the cytokines plus trypsin increased collagen degradation and conversion of the metalloproteinases to lower molecular weight forms corresponding to their active forms. Budesonide blocked both enhanced collagen degradation (P < 0.01) and suppressed trypsin-mediated conversion of cytokine-induced metalloproteinase-9 and metalloproteinase-3 to lower molecular weight forms. Similar effects were observed with dexamethasone 1 μM, suggesting a class effect. Conclusion: These findings demonstrate that budesonide directly modulates contraction of collagen gels and can decrease collagen degradation under inflammatory conditions. The mechanism of this effect is through suppressing gene expression, release, and activation of metalloproteinases. By modulating the release and activity of metalloproteinases, inhaled budesonide may be able to modify airway tissue repair and remodeling.

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