Canonical WNT pathway is activated in the airway epithelium in chronic obstructive pulmonary disease (original) (raw)
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Regulation of Wnt4 in chronic obstructive pulmonary disease
The FASEB Journal, 2013
Chronic obstructive pulmonary disease (COPD) is associated with persistent inflammation and oxidative stress in susceptible individuals. Using microarray analysis of bronchial biopsy samples from patients with COPD and controls, we identified Wnt4 as being up-regulated in COPD. Analysis of bronchial biopsy samples showed a very strong correlation between Wnt4 and IL8 gene expression, suggesting that Wnt4 plays a role in chronic lung inflammation. In vitro, Wnt4 induced proliferation and inflammation in human epithelial cells (BEAS-2B) and normal primary human bronchial epithelial cells in a concentration-dependent manner. This effect was enhanced in the presence of interleukin-1 (IL-1) as a result of activation of the p38 and c-Jun NH 2 -terminal kinase mitogen-activated protein kinase pathways. Hydrogen peroxide, but not proinflammatory stimuli, up-regulated Wnt4 expression in epithelial cells. In monocytic THP-1 and primary airway smooth muscle cells, Wnt4 induced inflammation and enhanced the inflammatory response to lipopolysaccharide and IL-1 but did not induce proliferation. In addition, these other cell types did not have enhanced Wnt4 expression in response to hydrogen peroxide. Our results indicate that airway epithelial activation, due to oxidative stress, may lead to Wnt4 induction. Wnt4, in turn, acts through the noncanonical pathway to activate epithelial cell remodeling and IL8 gene expression, leading to neutrophil infiltration and inflammationI. M. Regulation of Wnt4 in chronic obstructive pulmonary disease. FASEB J. 27,
Reduced Frizzled Receptor 4 Expression Prevents WNT/β-catenin-driven Alveolar Lung Repair in COPD
American journal of respiratory and critical care medicine, 2017
Chronic obstructive pulmonary disease (COPD), in particular emphysema, is characterized by loss of parenchymal alveolar tissue and impaired tissue repair. WNT/β-catenin signaling is reduced in COPD, however, the mechanisms thereof, specifically the role of WNT receptors Frizzled (FZD), remains unexplored. To identify and functionally characterize specific FZD receptors that control downstream WNT signaling in impaired lung repair in COPD. FZD receptor expression was analyzed in lung homogenates and primary alveolar epithelial type II (ATII) cells of never-smokers, smokers, and COPD patients, as well as two experimental emphysema models by qRT-PCR, immunoblotting, and immunofluorescence. The functional effects of cigarette smoke on WNT/β-catenin signaling and FZD4 function were investigated in primary ATII cells and cell lines. Gain- and loss-of-function approaches were applied to determine the effects of increased/decreased FZD4 expression on alveolar epithelial cell viability, woun...
A Role for Wnt Signaling Genes in the Pathogenesis of Impaired Lung Function in Asthma
American Journal of Respiratory and Critical Care Medicine, 2010
At-a-Glance Commentary: Scientific Knowledge on the Subject: The trajectory of lung function growth appears to be set early in life. Animal models demonstrate that abnormal in utero expression of genes implicated in normal lung development can result in abnormal pulmonary phenotypes after birth.
Wnt signalling in lung development and diseases
Respiratory research, 2006
There are several signalling pathways involved in lung organogenesis including Notch, TGFbeta/BMP, Sonic hedgehog (Shh), FGF, EGF, and Wnt. Despite the widely acknowledged significance of Wnt signalling in embryonic lung development, the role of different Wnt pathways in lung pathologies has been slow to emerge. In this review, we will present a synopsis of current Wnt research with particular attention paid to the role of Wnt signals in lung development and in pulmonary diseases.
Scientific Reports
COPD is characterised by poorly reversible airflow obstruction usually due to cigarette smoking. The transcription factor clusters of β-catenin/Snail1/Twist has been implicated in the process of epithelial mesenchymal transition (EMT), an intermediate between smoking and airway fibrosis, and indeed lung cancer. We have investigated expression of these transcription factors and their "cellular localization" in bronchoscopic airway biopsies from patients with COPD, and in smoking and non-smoking controls. An immune-histochemical study compared cellular protein expression of β-catenin, Snail1 and Twist, in these subject groups in 3 large airways compartment: epithelium (basal region), reticular basement membrane (Rbm) and underlying lamina propria (LP). β-catenin and Snail1 expression was generally high in all subjects throughout the airway wall with marked cytoplasmic to nuclear shift in COPD (P < 0.01). Twist expression was generalised in the epithelium in normal but become more basal and nuclear with smoking (P < 0.05). In addition, β-catenin and Snail1 expression, and to lesser extent of Twist, was related to airflow obstruction and to expression of a canonical EMT biomarker (S100A4). The β-catenin-Snail1-Twist transcription factor cluster is up-regulated and nuclear translocated in smokers and COPD, and their expression is closely related to both EMT activity and airway obstruction. Chronic obstructive pulmonary disease (COPD) is mainly smoking-related and primarily reflects small airway fibrosis and destruction with later development of emphysema in some. Approximately 50% of smokers develop COPD eventually 1, 2 and probably significantly more if specific small airway measurements are used 3 for assessment. COPD is also strongly related to lung cancer development 4-6. We and others have described active EMT in the airway epithelium smokers and especially in COPD 7-9. This is likely to be related to epithelial basal stem cell reprogramming 10. There is some work, mainly in epithelial cell culture on the mechanisms of EMT in the airways 11. But we also recently reported evidence in airway biopsies for involvement of TGF-β1 and its Smad transcription factor system 12. β-catenin is physiologically part of a major cell-surface adhesion complex 13 but if released from there becomes part of another important pro-pathological transcriptional factor cascade. This is classically induced by Wnt (Wingless tail) ligand activating the Frizzled cell surface receptor 14-16. We hypthesise that β-catenin may be involved in airway EMT activity, following a recent report of increased Wnt expression in lung epithelial cells from COPD patients 17. Binding of Wnt ligand to the Frizzled receptor induces its phosphorylation and through this inactivation of the cytoplasmic β-catenin sequester, glycogen synthase kinase-3β(GSK-3β) 18. This contributes to cytosolic accumulation of β-catenin and then nuclear translocation where it binds with lymphoid enhancing binding factor (LEF-1). In addition, TGF-β1 can signal to increase LEF-1 expression through SMADs and also to inhibit GSK-3β 19, 20 .
Aging Cell, 2014
In the aging lung, the lung capacity decreases even in the absence of diseases. The progenitor cells of the distal lung, the alveolar type II cells (ATII), are essential for the repair of the gas-exchange surface. Surfactant protein production and survival of ATII cells are supported by lipofibroblasts that are peroxisome proliferatoractivated receptor gamma (PPARc)-dependent special cell type of the pulmonary tissue. PPARc levels are directly regulated by Wnt molecules; therefore, changes in the Wnt microenvironment have close control over maintenance of the distal lung. The pulmonary aging process is associated with airspace enlargement, decrease in the distal epithelial cell compartment and infiltration of inflammatory cells. qRT-PCR analysis of purified epithelial and nonepithelial cells revealed that lipofibroblast differentiation marker parathyroid hormone-related protein receptor (PTHrPR) and PPARc are reduced and that PPARc reduction is regulated by Wnt4 via a b-catenin-dependent mechanism. Using a human in vitro 3D lung tissue model, a link was established between increased PPARc and pro-surfactant protein C (pro-SPC) expression in pulmonary epithelial cells. In the senile lung, both Wnt4 and Wnt5a levels increase and both Wnt-s increase myofibroblast-like differentiation. Alteration of the Wnt microenvironment plays a significant role in pulmonary aging. Diminished lipo-and increased myofibroblast-like differentiation are directly regulated by specific Wnt-s, which process also controls surfactant production and pulmonary repair mechanisms.
International Journal of Chronic Obstructive Pulmonary Disease, 2019
COPD is a common and highly destructive disease with huge impacts on people and health services throughout the world. It is mainly caused by cigarette smoking though environmental pollution is also significant. There are no current treatments that affect the overall course of COPD; current drugs focus on symptomatic relief and to some extent reducing exacerbation rates. There is an urgent need for in-depth studies of the fundamental pathogenic mechanisms that underpin COPD. This is vital, given the fact that nearly 40%-60% of the small airway and alveolar damage occurs in COPD well before the first measurable changes in lung function are detected. These individuals are also at a high risk of lung cancer. Current COPD research is mostly centered around late disease and/or innate immune activation within the airway lumen, but the actual damage to the airway wall has early onset. COPD is the end result of complex mechanisms, possibly triggered through initial epithelial activation. To change the disease trajectory, it is crucial to understand the mechanisms in the epithelium that are switched on early in smokers. One such mechanism we believe is the process of epithelial to mesenchymal transition. This article highlights the importance of this profound epithelial cell plasticity in COPD and also its regulation. We consider that understanding early changes in COPD will open new windows for therapy.