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Asthma is a serious public health problem worldwide, without effective therapeutic methods. Our previous study indicated that glucocorticoid-induced transcript 1 gene (GLCCI1) knockout reduces the sensitivity to glucocorticoid in asthmatic mouse. Here, we explored the role and action mechanism of GLCCI1 in asthma development. In ovalbumin-sensitized mice, airway resistance and tissue damage increased, the production of inflammatory cytokines were up-regulated, GLCCI1 expression was reduced and autophagy was activated. Increasing of GLCCI1 inhibited human and mouse airway epithelial cell (AEC) autophagy, while decreasing of GLCCI1 promoted autophagy. Furthermore, we found that GLCCI1 bound with WD repeat domain 45B (WDR45B) and inhibited its expression. Increasing of WDR45B partly reversed the inhibition of GLCCI1 to autophagy-related proteins expression and autophagosome formation in vitro. Increasing of WDR45B in vivo reversed the improvement of GLCCI1 on airway remodelling in asthma and the inhibition to autophagy level in lung tissues. Overall, our data showed that GLCCI1 improved airway remodelling in ovalbumin-sensitized mice through inhibiting autophagy via combination with WDR45B and inhibiting its expression. Our results proved a new idea for asthma treatment., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma., Methods: We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry., Results: Using stringent false discovery rate analysis, MMP-10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP-10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less-stringent conditions (raw P-value < 0.05, log2 fold change > 0.5), we defined a 73-gene set characteristic of the HE compared to the LE group. Thirty-three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC-chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS-1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression., Conclusion: Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP-10 likely play an important role in these processes., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Aberrant activation of β-catenin signaling by both WNT-dependent and WNT-independent pathways has been demonstrated in asthmatic airways, which is thought to contribute critically in remodeling of the airways. Yet, the exact role of β-catenin in asthma is very poorly defined. As we have previously reported abnormal expression of β-catenin in a toluene diisocyanate (TDI)-induced asthma model, in this study, we evaluated the therapeutic efficacy of two small molecules XAV-939 and ICG-001 in TDI-asthmatic male BALB/c mice, which selectively block β-catenin-mediated transcription., Methods: Male BALB/c mice were sensitized and challenged with TDI to generate a chemically induced asthma model. Inhibitors of β-catenin, XAV-939, and ICG-001 were respectively given to the mice through intraperitoneally injection., Results: TDI exposure led to a significantly increased activity of β-catenin, which was then confirmed by a luciferase assay in 16HBE transfected with the TOPFlash reporter plasmid. Treatment with either XAV-939 or ICG-001 effectively inhibited activation of β-catenin and downregulated mRNA expression of β-catenin-targeted genes in TDI-asthmatic mice, paralleled by dramatically attenuated TDI-induced hyperresponsiveness and inflammation of the airway, alleviated airway goblet cell metaplasia and collagen deposition, decreased Th2 inflammation, as well as lower levels of TGFβ1, VEGF, HMGB1, and IL-1β., Conclusion: The results showed that β-catenin is a principal mediator of TDI-induced asthma, proposing β-catenin as a promising therapeutic target in asthma., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Increased proliferation of airway smooth muscle (ASM) cells leading to hyperplasia and increased ASM mass is one of the most characteristic features of airway remodelling in asthma. A bioactive lipid, sphingosine-1-phosphate (S1P), has been suggested to affect airway remodelling by stimulation of human ASM cell proliferation., Objective: To investigate the effect of S1P on signalling and regulation of gene expression in ASM cells from healthy and asthmatic individuals., Methods: Airway smooth muscle cells grown from bronchial biopsies of healthy and asthmatic individuals were exposed to S1P. Gene expression was analysed using microarray, real-time PCR and Western blotting. Receptor signalling and function were determined by mRNA knockdown and intracellular calcium mobilization experiments., Results: S1P potently regulated the expression of more than 80 genes in human ASM cells, including several genes known to be involved in the regulation of cell proliferation and airway remodelling (HBEGF, TGFB3, TXNIP, PLAUR, SERPINE1, RGS4). S1P acting through S1P2 and S1P3 receptors activated intracellular calcium mobilization and extracellular signal-regulated and Rho-associated kinases to regulate gene expression. S1P-induced responses were not inhibited by corticosteroids and did not differ significantly between ASM cells from healthy and asthmatic individuals., Conclusion: S1P induces a steroid-resistant, pro-remodelling pathway in ASM cells. Targeting S1P or its receptors could be a novel treatment strategy for inhibiting airway remodelling in asthma., (© 2014 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Background: The current paradigm describing asthma pathogenesis recognizes the central role of abnormal epithelial function in the generation and maintenance of the disease. However, the mechanisms responsible for the initiation of airway remodeling, which contributes to decreased lung function, remain elusive. Therefore, we aimed to determine the role of altered pulmonary gene expression in disease inception and identify proremodeling mediators., Methods: Using an adenoviral vector, we generated mice overexpressing smad2, a TGF-β and activin A signaling molecule, in the lung. Animals were exposed to intranasal ovalbumin (OVA) without systemic sensitization., Results: Control mice exposed to inhaled OVA showed no evidence of pulmonary inflammation, indices of remodeling, or airway hyper-reactivity. In contrast, local smad2 overexpression provoked airway hyper-reactivity in OVA-treated mice, concomitant with increased airway smooth muscle mass and peribronchial collagen deposition. Pulmonary eosinophilic inflammation was not evident, and there was no change in serum IgE or IgG1 levels. The profound remodeling changes were not mediated by classical pro-inflammatory Th2 cytokines. However, uric acid and interleukin-1β levels in the lung were increased. Epithelial-derived endothelin-1 and fibroblast growth factor were also augmented in smad2-expressing mice. Blocking endothelin-1 prevented these phenotypic changes., Conclusions: Innate epithelial-derived mediators are sufficient to drive airway hyper-reactivity and remodeling in response to environmental insults in the absence of overt Th2-type inflammation in a model of noneosinophilic, noninflammed types of asthma. Targeting potential asthma therapies to epithelial cell function and modulation of locally released mediators may represent an effective avenue for therapeutic design., (© 2013 The Authors. Allergy published by John Wiley & Sons Ltd.)

This study aimed to identify the role and regulation of thymic stromal lymphopoietin (TSLP) in asthmatic airway remodelling. To identify the expression of TSLP, α smooth muscle actin (α-SMA) and collagen I in bronchial tissues, bronchial biopsy specimens were collected from patients with asthma and healthy controls and stained with specific antibodies, respectively. To characterize the signalling pathways regulated by TSLP, we silenced or overexpressed TSLP in human lung fibroblast (HLF-1) cells by shRNA approaches or transfection and detected the expression of TSLP receptor (TSLPR) by enzyme-linked immunosorbent assay and Western blot analysis. In TSLP signalling pathway, the protein expression of total signal transducer and activator of transcription 3 (STAT3), STAT5, the phosphorylation of STAT3 (pSTAT3) and STAT5 (pSTAT5), TSLP, α-SMA and collagen I were also detected by Western blotting. In addition, the α-SMA, collagen I and mRNA expression were determined by real-time reverse-transcription. To further confirm the TSLP-STAT3 signalling pathway in HLF-1 cells, we inhibited STAT3 activity by targeted small molecules and then detected TSLP-induced expression of α-SMA and collagen I in both mRNA and protein levels by quantitative real-time reverse-transcription and Western blotting, respectively. First, overexpression of TSLP, α-SMA and collagen I was detected in epithelium collected from patients with asthma. Second, STAT3 activity and the expression of α-SMA and collagen I were controlled, regulated by TSLP. Specifically, the pSTAT3, α-SMA and collagen I were induced by the introduction of TSLP in HLF-1 cells, and the repression of α-SMA and collagen I was detected after TSLP silencing. Third, no changes of pSTAT5 were found in the presence of the STAT3 inhibitor, and TSLP-induced α-SMA and collagen I upregulation is in a STAT3 dependent manner. If we inhibit STAT3 activity by STAT3 targeted small molecules, TSLP-induced α-SMA and collagen I upregulation cannot be detected. The functions of TSLP in asthmatic airway remodelling were performed through STAT3 signalling pathway., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: Transforming growth factor (TGF)-β1 produced in airway epithelia has been suggested as a contributor to the airway remodeling observed in asthma patients. The protein tyrosine phosphatase SHP2 is a demonstrable modulator of TGF-β1 production and thus a potential regulator of airway remodeling., Objectives: To define the signal event by which SHP2 regulates asthmatic responses in airway epithelial cells by using a mouse model of experimental OVA-induced airway remodeling., Methods: The airways of Shp2(flox/flox) mice were infected with recombinant adenovirus vectors expressing a Cre recombinase-green fluorescence protein (GFP) fusion protein as part of allergen provocation studies using mice sensitized with ovalbumin (OVA) and repeatedly challenged with OVA. Several endpoint pathologies were assessed, including airway hyper-responsiveness (AHR), lung inflammatory score, peribronchial collagen deposition, and α-smooth muscle actin (SMA) hyperplasia. In vitro studies using airway epithelial cells (BEAS-2B) were used to investigate the role of SHP2 in the regulation of pulmonary remodeling events, including the expression of collagen, α-SMA, and TGF-β1., Results: Chronic OVA challenges in wild-type mice resulted in airway remodeling and lung dysfunction (e.g., increased inflammatory scores, collagen deposition (fibrosis), smooth muscle hyperplasia, and a significant increase in AHR). These endpoint pathology metrics were each significantly attenuated by conditional shp2 gene knockdown in airway epithelia. In vitro studies using BEAS-2B cells also demonstrated that the level of TGF-β1 production by these cells correlated with the extent of shp2 gene expression., Conclusions: SHP2 activities in airway epithelial cells appear to modulate TGF-β1 production and, in turn, regulate allergic airway remodeling following allergen provocation., Clinical Implications: Our findings identify SHP2 as a previously underappreciated contributor to the airway remodeling and lung dysfunction associated with allergen challenge. As such, SHP2 represents a potentially novel therapeutic target for the treatment of asthmatics., Capsule Summary: Airway epithelial protein tyrosine phosphatase SHP2 appears to modulate TGF-β1 activities as part of one or more cellular pathways leading to regulating the airway remodeling and lung dysfunction occurring in mouse models of allergic respiratory inflammation., (© 2012 John Wiley & Sons A/S.)