Overexpression of the hyperplasia suppressor gene inactivates airway fibroblasts obtained from a rat model of chronic obstructive pulmonary disease by inhibiting the Wnt signaling pathway

Abstract

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.

Ardisia japonica inhibits airway remodeling in chronic obstructive pulmonary disease in rats through inhibiting Wnt signaling pathway

“…We have previously reported that hyperplasia suppressor gene (HSG) overexpression inactivated airway broblasts from COPD by inhibiting the Wnt signaling pathway (51). In this study, we also provided in vivo data showing that AJ in different doses ameliorated airway remodeling and antagonized Wnt signaling pathway.…”

“…Using the cultured airway broblasts obtained from COPD model, we further veri ed that Wnt agonists LiCl and HLY78 promoted the cell proliferation and reduced apoptosis. We could speculate that the antagonists of Wnt signaling pathway would block the cell proliferation and promote apoptosis, like the effect of HSG overexpression (51). Additionally, MAPK pathway agonists also exhibited the similar functions as Wnt signaling pathway agonists.…”

Deflamin Attenuated Lung Tissue Damage in an Ozone-Induced COPD Murine Model by Regulating MMP-9 Catalytic Activity

“…Pulmonary emphysema is related to inflammation [4,5] and cell senescence, which subsequently leads to pneumocyte death and degradation of the extracellular matrix (ECM) [6][7][8]. On the other hand, peribronchial fibrosis is mainly a response to the process of epithelial-mesenchymal transition (EMT) mediated by the disruption of the lung cell basement membrane, and it is widely regulated by the transforming growth factor β (TGF-β) signaling pathway [9,10]. Interestingly, regardless of the etiology and molecular mechanisms underlying these pathological changes, metalloproteinases, a family of zinc-dependent endoproteinases, have a predominant role in both processes: these molecules have been reported to be some of the major effector enzymes of COPD lung tissue remodeling [11].…”

“…Gelatinase B also plays a regulatory role in inflammation and fibrosis by catalyzing the activation of important molecules, such as pro-tumor necrosis factor-α (TNF-α) [24], pro-interleukin 1β (IL-1β) [25] and pro-TGF-β [26]. Additionally, MMP-9 has also been associated with mechanisms of COPD perpetuation [27], lung cancer progression [9,10], and acute exacerbations of COPD (AE-COPD), characterized by worsening of lung function and increased susceptibility to respiratory infections [28,29].…”

Mechanistic Regulation of Wnt Pathway-Related Progression of Chronic Obstructive Pulmonary Disease Airway Lesions

“…65 In fibroblasts, hyperplasia suppressor gene (HSG) is found to inhibit airway remodeling in COPD by inhibiting the Wnt pathway and reducing beta-catenin expression to reduce cell viability. 66 Reduced levels of DKK1, an endogenous inhibitor of Wnt, are seen as more positive changes in lung function in COPD patients. 67 Studies show that in primary human airway smooth muscle cells, activation of Wnt/beta-catenin signaling pathway participates in TGF-beta-induced ECM protein deposition, including increased expressions of collagen I, fibronectin, multifunctional proteoglycan, laminin, and core proteoglycan, providing new insights for the occurrence and development of airway remodeling in lung diseases.…”