Unique mechanisms of connective tissue growth factor regulation in airway smooth muscle in asthma: Relationship with airway remodelling.
Junfei WangAlen FaizQi GeCornelis J VermeulenJoanne Van der VeldenKenneth J SnibsonRob van de VeldeSonia SawantDikaia XenakiBrian OliverWim TimensNick Ten HackenMaarten van den BergeAlan JamesJohn G ElliotLiang DongJanette K BurgessAnthony W AshtonPublished in: Journal of cellular and molecular medicine (2018)
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.
Keyphrases
- gene expression
- growth factor
- transforming growth factor
- transcription factor
- induced apoptosis
- smooth muscle
- dna methylation
- poor prognosis
- cell cycle arrest
- chronic obstructive pulmonary disease
- binding protein
- lung function
- oxidative stress
- cell death
- allergic rhinitis
- ejection fraction
- long non coding rna
- prognostic factors
- pi k akt
- cell proliferation
- ultrasound guided
- endothelial cells