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Activation of WNT/?-catenin signaling in pulmonary fibroblasts by TGF-?? is increased in chronic obstructive pulmonary disease.

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterized by abnormal extracellular matrix (ECM) turnover. Recently, activation of the WNT/?-catenin pathway has been associated with abnormal ECM turnover in various chronic diseases. We determined WNT-pathway gene expression in pulmonary fibroblasts of individuals with and without COPD and disentangled the role of ?-catenin in fibroblast phenotype and function.We assessed the expression of WNT-pathway genes and the functional role of ?-catenin, using MRC-5 human lung fibroblasts and primary pulmonary fibroblasts of individuals with and without COPD.Pulmonary fibroblasts expressed mRNA of genes required for WNT signaling. Stimulation of fibroblasts with TGF-??, a growth factor important in COPD pathogenesis, induced WNT-5B, FZD?, DVL3 and ?-catenin mRNA expression. The induction of WNT-5B, FZD?, FZD? and DVL3 mRNA by TGF-?? was higher in fibroblasts of individuals with COPD than without COPD, whilst basal expression was similar. Accordingly, TGF-?? activated ?-catenin signaling, as shown by an increase in transcriptionally active and total ?-catenin protein expression. Furthermore, TGF-??induced the expression of collagen1?1, ?-sm-actin and fibronectin, which was attenuated by ?-catenin specific siRNA and by pharmacological inhibition of ?-catenin, whereas the TGF-??-induced expression of PAI-1 was not affected. The induction of transcriptionally active ?-catenin and subsequent fibronectin deposition induced by TGF-?? were enhanced in pulmonary fibroblasts from individuals with COPD.?-catenin signaling contributes to ECM production by pulmonary fibroblasts and contributes to myofibroblasts differentiation. WNT/?-catenin pathway expression and activation by TGF-?? is enhanced in pulmonary fibroblasts from individuals with COPD. This suggests an important role of the WNT/?-catenin pathway in regulating fibroblast phenotype and function in COPD.

SUBMITTER: Baarsma HA

PROVIDER: S-EPMC3184127 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Activation of WNT/β-catenin signaling in pulmonary fibroblasts by TGF-β₁ is increased in chronic obstructive pulmonary disease.

Baarsma Hoeke A HA Spanjer Anita I R AI Haitsma Gertruud G Engelbertink Lilian H J M LH Meurs Herman H Jonker Marnix R MR Timens Wim W Postma Dirkje S DS Kerstjens Huib A M HA Gosens Reinoud R

PloS one 20110930 9

<h4>Background</h4>Chronic obstructive pulmonary disease (COPD) is characterized by abnormal extracellular matrix (ECM) turnover. Recently, activation of the WNT/β-catenin pathway has been associated with abnormal ECM turnover in various chronic diseases. We determined WNT-pathway gene expression in pulmonary fibroblasts of individuals with and without COPD and disentangled the role of β-catenin in fibroblast phenotype and function.<h4>Methods</h4>We assessed the expression of WNT-pathway genes ...[more]

PMID: 21980461

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Project description:The present study aimed to investigate the effects of hyperplasia suppressor gene (HSG) overexpression on the activation of airway fibroblasts in a rat model of chronic obstructive pulmonary disease (COPD) and assess the underlying molecular mechanisms. The rat model of COPD was established by injection of papain and confirmed by hematoxylin and eosin staining. Airway fibroblasts were identified using immunofluorescence, and HSG expression was facilitated by an HSG vector. Cell viability, apoptosis and the levels of matrix metallopeptidase‑9 (MMP‑9), platelet‑derived growth factor (PDGF), and transforming growth factor‑β1 (TGF‑β1) were measured via Cell Counting Kit‑8, flow cytometry and ELISA analyses, respectively, and potential mechanisms were detected by reverse transcription‑quantitative polymerase chain reaction and western blotting. Airway fibroblasts from COPD rats were isolated and identified based on vimentin expression. Compared with the control group, HSG overexpression reduced cell viability, promoted apoptosis, and reduced the protein levels of TGF‑β1, MMP‑9 and PDGF. Additionally, HSG overexpression reduced β‑catenin and Ras homology family member A (RhoA) expression at both the mRNA and protein levels. Conversely, Wnt signaling pathway agonists lithium chloride (LiCl) and 4‑ethyl‑5,6‑dihydro‑5‑methyl‑(1,3)dioxolo(4,5‑j)phenanthridine (HLY78), significantly reduced the effects of HSG overexpression (P<0.05 vs. HSG). Cell viability in the HSG + LiCl and HSG + HLY78 groups was increased, whereas apoptosis was reduced compared with HSG treatment alone. The protein levels of TGF‑β1, MMP‑9 and PDGF were also decreased in the HSG + LiCl and HSG + HLY78 groups compared with the HSG group (P<0.05). Furthermore, the expression of β‑catenin and RhoA was higher in the HSG + LiCl and HSG + HLY78 groups compared with the HSG group (P<0.05). Collectively, the results indicated that HSG overexpression inactivated airway fibroblasts from COPD by inhibiting the Wnt signaling pathway.

Project description:PurposePulmonary hypertension (PH) is characterized by a progressive remodelling of the pulmonary vasculature resulting in right heart failure and eventually death. The serotonin transporter (SERT) may be involved in the pathogenesis of PH in patients with chronic-obstructive pulmonary disease (COPD). This study investigated for the first time the SERT in vivo availability in the lungs of patients with COPD and PH (COPD+PH).MethodsSERT availability was assessed using SERT-selective [11C]DASB and positron emission tomography/computed tomography (PET/CT) with dynamic acquisition over 30 min in 4 groups of 5 participants each: COPD, COPD+PH, pulmonary arterial hypertension, and a healthy control (HC). Time activity curves were generated based on a volume of interest within the middle lobe. Tissue-to-blood concentration ratios after 25 to 30 min (TTBR25-30) served as receptor parameter for group comparison and were corrected for lung tissue attenuation. Participants underwent comprehensive pulmonary workup. Statistical analysis included group comparisons and correlation analysis.Results[11C]DASB uptake peak values did not differ among the cohorts after adjusting for lung tissue attenuation, suggesting equal radiotracer delivery. Both the COPD and COPD+PH cohort showed significantly lower TTBR25-30 values after correction for lung attenuation than HC. Attenuation corrected TTBR25-30 values were significantly higher in the COPD+PH cohort than those in the COPD cohort and higher in non-smokers than in smokers. They positively correlated with invasively measured severity of PH and inversely with airflow limitation and emphysema. Considering all COPD patients ± PH, they positively correlated with right heart strain (NT-proBNP).ConclusionBy applying [11C]DASB and PET/CT, semiquantitative measures of SERT availability are demonstrated in the lung vasculature of patients with COPD and/or PH. COPD patients who developed PH show increased pulmonary [11C]DASB uptake compared to COPD patients without PH indicating an implication of pulmonary SERT in the development of PH in COPD patients.

Dataset Information

Activation of WNT/?-catenin signaling in pulmonary fibroblasts by TGF-?? is increased in chronic obstructive pulmonary disease.

Publications

Activation of WNT/β-catenin signaling in pulmonary fibroblasts by TGF-β₁ is increased in chronic obstructive pulmonary disease.

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