Unique mechanisms of connective tissue growth factor regulation in airway smooth muscle in asthma: Relationship with airway remodelling

Wang, J; Faiz, A; Ge, Q; Vermeulen, CJ; Van der Velden, J; Snibson, KJ; van de Velde, R; Sawant, S; Xenaki, D; Oliver, B; Timens, W; ten Hacken, N; van den Berge, M; James, A; Elliot, JG; Dong, L; Burgess, JK; Ashton, AW

Unique mechanisms of connective tissue growth factor regulation in airway smooth muscle in asthma: Relationship with airway remodelling

Wang, J Faiz, A

Ge, Q Vermeulen, CJ Van der Velden, J Snibson, KJ van de Velde, R Sawant, S Xenaki, D Oliver, B

Timens, W ten Hacken, N van den Berge, M James, A Elliot, JG Dong, L Burgess, JK Ashton, AW

Permalink

Publication Type:: Journal Article
Citation:: Journal of Cellular and Molecular Medicine, 2018, 22 (5), pp. 2826 - 2837
Issue Date:: 2018-05-01

Open Access

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is open access.

Adobe PDF

Download Accepted Manuscript VersionAdobe PDF (1.18 MB)

View on publisher's site

View statistics

Full metadata record

Field	Value	Language
dc.contributor.author	Wang, J	en_US
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538	en_US
dc.contributor.author	Ge, Q	en_US
dc.contributor.author	Vermeulen, CJ	en_US
dc.contributor.author	Van der Velden, J	en_US
dc.contributor.author	Snibson, KJ	en_US
dc.contributor.author	van de Velde, R	en_US
dc.contributor.author	Sawant, S	en_US
dc.contributor.author	Xenaki, D	en_US
dc.contributor.author	Oliver, B https://orcid.org/0000-0002-7122-9262	en_US
dc.contributor.author	Timens, W	en_US
dc.contributor.author	ten Hacken, N	en_US
dc.contributor.author	van den Berge, M	en_US
dc.contributor.author	James, A	en_US
dc.contributor.author	Elliot, JG	en_US
dc.contributor.author	Dong, L	en_US
dc.contributor.author	Burgess, JK	en_US
dc.contributor.author	Ashton, AW	en_US
dc.date.available	2018-01-29	en_US
dc.date.issued	2018-05-01	en_US
dc.identifier.citation	Journal of Cellular and Molecular Medicine, 2018, 22 (5), pp. 2826 - 2837	en_US
dc.identifier.issn	1582-1838	en_US
dc.identifier.uri	http://hdl.handle.net/10453/123446
dc.description.abstract	© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. Neovascularization, increased basal membrane thickness and increased airway smooth muscle (ASM) bulk are hallmarks of airway remodelling in asthma. In this study, we examined connective tissue growth factor (CTGF) dysregulation in human lung tissue and animal models of allergic airway disease. Immunohistochemistry revealed that ASM cells from patients with severe asthma (A) exhibited high expression of CTGF, compared to mild and non-asthmatic (NA) tissues. This finding was replicated in a sheep model of allergic airways disease. In vitro, transforming growth factor (TGF)-β increased CTGF expression both in NA- and A-ASM cells but the expression was higher in A-ASM at both the mRNA and protein level as assessed by PCR and Western blot. Transfection of CTGF promoter-luciferase reporter constructs into NA- and A-ASM cells indicated that no region of the CTGF promoter (−1500 to +200 bp) displayed enhanced activity in the presence of TGF-β. However, in silico analysis of the CTGF promoter suggested that distant transcription factor binding sites may influence CTGF promoter activation by TGF-β in ASM cells. The discord between promoter activity and mRNA expression was also explained, in part, by differential post-transcriptional regulation in A-ASM cells due to enhanced mRNA stability for CTGF. In patients, higher CTGF gene expression in bronchial biopsies was correlated with increased basement membrane thickness indicating that the enhanced CTGF expression in A-ASM may contribute to airway remodelling in asthma.	en_US
dc.relation.ispartof	Journal of Cellular and Molecular Medicine	en_US
dc.relation.isbasedon	10.1111/jcmm.13576	en_US
dc.subject.classification	Biochemistry & Molecular Biology	en_US
dc.subject.mesh	Muscle, Smooth	en_US
dc.subject.mesh	Lung	en_US
dc.subject.mesh	Basement Membrane	en_US
dc.subject.mesh	Myocytes, Smooth Muscle	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Sheep	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Pyroglyphidae	en_US
dc.subject.mesh	Asthma	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Base Pairing	en_US
dc.subject.mesh	RNA Stability	en_US
dc.subject.mesh	Adolescent	en_US
dc.subject.mesh	Adult	en_US
dc.subject.mesh	Aged	en_US
dc.subject.mesh	Aged, 80 and over	en_US
dc.subject.mesh	Middle Aged	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Promoter Regions, Genetic	en_US
dc.subject.mesh	Connective Tissue Growth Factor	en_US
dc.subject.mesh	Young Adult	en_US
dc.subject.mesh	Airway Remodeling	en_US
dc.title	Unique mechanisms of connective tissue growth factor regulation in airway smooth muscle in asthma: Relationship with airway remodelling	en_US
dc.type	Journal Article
utslib.citation.volume	5	en_US
utslib.citation.volume	22	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1103 Clinical Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	open_access
pubs.issue	5	en_US
pubs.publication-status	Published	en_US
pubs.volume	22	en_US

Abstract:

© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. Neovascularization, increased basal membrane thickness and increased airway smooth muscle (ASM) bulk are hallmarks of airway remodelling in asthma. In this study, we examined connective tissue growth factor (CTGF) dysregulation in human lung tissue and animal models of allergic airway disease. Immunohistochemistry revealed that ASM cells from patients with severe asthma (A) exhibited high expression of CTGF, compared to mild and non-asthmatic (NA) tissues. This finding was replicated in a sheep model of allergic airways disease. In vitro, transforming growth factor (TGF)-β increased CTGF expression both in NA- and A-ASM cells but the expression was higher in A-ASM at both the mRNA and protein level as assessed by PCR and Western blot. Transfection of CTGF promoter-luciferase reporter constructs into NA- and A-ASM cells indicated that no region of the CTGF promoter (−1500 to +200 bp) displayed enhanced activity in the presence of TGF-β. However, in silico analysis of the CTGF promoter suggested that distant transcription factor binding sites may influence CTGF promoter activation by TGF-β in ASM cells. The discord between promoter activity and mRNA expression was also explained, in part, by differential post-transcriptional regulation in A-ASM cells due to enhanced mRNA stability for CTGF. In patients, higher CTGF gene expression in bronchial biopsies was correlated with increased basement membrane thickness indicating that the enhanced CTGF expression in A-ASM may contribute to airway remodelling in asthma.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/123446