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

Qiuhong Fang,1,2 Nancy A Schulte,3 Huijung Kim,4 Tetsu Kobayashi,5 Xingqi Wang,2 Anna Miller-Larsson,6 Elisabet Wieslander,6 Myron L Toews,3 Xiangde Liu,2 Stephen I Rennard21Pulmonary and Critical Care Department, Beijing Shijitan Hospital, Capital Medical University, Beijing, People&#39;s R...

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Autores principales:	Fang Q, Schulte NA, Kim H, Kobayashi T, Wang X, Miller-Larsson A, Wieslander E, Toews ML, Liu X, Rennard SI
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2013
Materias:	Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/bf3b635fa32e43aa869e5060784918a3
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spelling	oai:doaj.org-article:bf3b635fa32e43aa869e5060784918a32021-12-02T01:26:35ZEffect of budesonide on fibroblast-mediated collagen gel contraction and degradation1178-7031https://doaj.org/article/bf3b635fa32e43aa869e5060784918a32013-02-01T00:00:00Zhttp://www.dovepress.com/effect-of-budesonide-on-fibroblast-mediated-collagen-gel-contraction-a-a12313https://doaj.org/toc/1178-7031Qiuhong Fang,1,2 Nancy A Schulte,3 Huijung Kim,4 Tetsu Kobayashi,5 Xingqi Wang,2 Anna Miller-Larsson,6 Elisabet Wieslander,6 Myron L Toews,3 Xiangde Liu,2 Stephen I Rennard21Pulmonary and Critical Care Department, Beijing Shijitan Hospital, Capital Medical University, Beijing, People&#39;s Republic of China; 2Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 3Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA; 4Pulmonary and Critical Care Division, WonKwang University, Kunpo Medical Center, Seoul, Republic of Korea; 5Mie University Graduate School of Medicine, Tsu City, Japan; 6AstraZeneca R&amp;D Molndal, Molndal, SwedenBackground: 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&ndash;1000 nM) on collagen gel contraction and degradation in the presence or absence of inflammatory cytokines (interleukin-1&beta; and tumor necrosis factor &alpha;; 5 ng/mL each) and, in order to activate latent proteases, serine protease trypsin 0.25 &micro;g/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 &lt; 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 &lt; 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 &lt; 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 &micro;M, 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.Keywords: metalloproteinase, budesonide, tissue remodelingFang QSchulte NAKim HKobayashi TWang XMiller-Larsson AWieslander EToews MLLiu XRennard SIDove Medical PressarticlePathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol 2013, Iss default, Pp 25-33 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Fang Q Schulte NA Kim H Kobayashi T Wang X Miller-Larsson A Wieslander E Toews ML Liu X Rennard SI Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation
description	Qiuhong Fang,1,2 Nancy A Schulte,3 Huijung Kim,4 Tetsu Kobayashi,5 Xingqi Wang,2 Anna Miller-Larsson,6 Elisabet Wieslander,6 Myron L Toews,3 Xiangde Liu,2 Stephen I Rennard21Pulmonary and Critical Care Department, Beijing Shijitan Hospital, Capital Medical University, Beijing, People&#39;s Republic of China; 2Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 3Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA; 4Pulmonary and Critical Care Division, WonKwang University, Kunpo Medical Center, Seoul, Republic of Korea; 5Mie University Graduate School of Medicine, Tsu City, Japan; 6AstraZeneca R&amp;D Molndal, Molndal, SwedenBackground: 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&ndash;1000 nM) on collagen gel contraction and degradation in the presence or absence of inflammatory cytokines (interleukin-1&beta; and tumor necrosis factor &alpha;; 5 ng/mL each) and, in order to activate latent proteases, serine protease trypsin 0.25 &micro;g/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 &lt; 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 &lt; 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 &lt; 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 &micro;M, 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.Keywords: metalloproteinase, budesonide, tissue remodeling
format	article
author	Fang Q Schulte NA Kim H Kobayashi T Wang X Miller-Larsson A Wieslander E Toews ML Liu X Rennard SI
author_facet	Fang Q Schulte NA Kim H Kobayashi T Wang X Miller-Larsson A Wieslander E Toews ML Liu X Rennard SI
author_sort	Fang Q
title	Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation
title_short	Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation
title_full	Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation
title_fullStr	Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation
title_full_unstemmed	Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation
title_sort	effect of budesonide on fibroblast-mediated collagen gel contraction and degradation
publisher	Dove Medical Press
publishDate	2013
url	https://doaj.org/article/bf3b635fa32e43aa869e5060784918a3
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Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation

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