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pISSN 2092-7355   eISSN 2092-7363
    Allergy Asthma Immunol Res. 2024 Jul;16(4):422-433. English.
    Published online May 21, 2024.
    https://doi.org/10.4168/aair.2024.16.4.422
    Copyright © 2024 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease
    Brief Communication

    LincR-PPP2R5C Deficiency Alleviates Airway Remodeling by Inhibiting Epithelial-Mesenchymal Transition Through the PP2A/TGF-β1 Signaling Pathway in Chronic Experimental Allergic Asthma

    Qi Yuan,1 Xinyu Jia,1 Min Wang,1 Zhongqi Chen,1 Tingting Xu,1 Xijie Zhang,1 Yanan Liu,1 Zhengxia Wang,1 Chen Yang,2 Mingshun Zhang,2 Wei Zhang,3 Mao Huang,1 and Ningfei Ji1
      • 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
      • 2NHC Key Laboratory of Antibody Technique, Department of Immunology, Nanjing Medical University, Nanjing, China.
      • 3Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
    • Correspondence to Mingshun Zhang, MD, PhD. NHC Key Laboratory of Antibody Technique, Department of Immunology, Nanjing Medical University, 101 Longmian Street, Nanjing 211166, China. Tel: +86-25-8686-3176; Fax: +86-25-8686-3176; Email: mingshunzhang@njmu.edu.cn
      Correspondence to Wei Zhang, MD. Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China. Tel: +86-25-8371-4511; Fax: +86-25-8371-4511; Email: fskzhangwei@126.com
      Correspondence to Mao Huang, MD. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China. Tel: +86-25-8371-4511; Fax: +86-25-8371-4511; Email: hm6114@163.com
      Correspondence to Ningfei Ji, MD. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China. Tel: +86-25-8371-4511; Fax: +86-25-8371-4511; Email: jiningfei@163.com
    Received November 01, 2023; Revised January 13, 2024; Accepted February 21, 2024.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Airway remodeling is a key characteristic of allergic asthma. Epithelial-mesenchymal transition (EMT) induced by various factors, particularly transforming growth factor (TGF)-β1, orchestrates airway remodeling. Protein phosphatase 2A (PP2A), an important serine-threonine phosphatase, is involved in TGF-β1 production and EMT. Long noncoding RNAs (lncRNAs) have emerged as novel players in regulating EMT. Here, we aimed to explore the effects and mechanisms of action of lincR-PPP2R5C, a lncRNA that affects PP2A activity, on airway remodeling in a mouse model of chronic allergic asthma. LincR-PPP2R5C knockout (KO) alleviated inflammatory responses in house dust mite (HDM)-induced chronic allergic asthma. Moreover, airway remodeling and EMT were reduced in lung tissues of lincR-PPP2R5C KO mice. HDM extract induced EMT in airway epithelial cells, which was decreased following lincR-PPP2R5C KO. Mechanistically, lincR-PPP2R5C deficiency enhanced PP2A activity, which inhibited TGF-β1 production in epithelial cells. In conclusion, lincR-PPP2R5C deficiency prevented HDM-induced airway remodeling in mice by reversing EMT, which was mediated by the PP2A/TGF-β1 signaling pathway. Thus, lncRNAs, i.e., lincR-PPP2R5C, may be potential targets to prevent airway remodeling in allergic asthma.

    Keywords
    Asthma; long noncoding RNA; airway remodeling; transforming growth factor-β1; protein phosphatase 2A

    INTRODUCTION

    Asthma is a chronic respiratory disorder, and the global incidence of asthma has risen in recent years.1 Airway remodeling is a key feature of asthma,2, 3 which is characterized by epithelial injury, subepithelial thickening and fibrosis, smooth muscle hypertrophy, and collagen deposition.4 The impact of current clinical pharmacological therapies on airway structure remains largely unknown. Epithelial-mesenchymal Transition (EMT) plays an essential role in airway remodeling.5 Therefore, exploring the underlying molecular mechanisms of EMT and finding effective strategies for attenuating airway remodeling may be beneficial for preventing and treating asthma.

    In recent years, long noncoding RNAs (lncRNAs) have been implicated in regulating various biological processes in asthma.6 Recently, we have identified the involvement of lncRNAs in the pathogenesis of asthma.7 Of note, ablation of lincR-PPP2R5C inhibits T helper 2 (Th2) differentiation by affecting the activity of protein phosphatase 2A (PP2A) in a mouse model of acute asthma, thereby alleviating airway inflammation.8 However, the roles and mechanisms of lincR-PPP2R5C in epithelial cells and airway remodeling during allergic asthma remain unclear.

    This study aimed to elucidate the roles of lincR-PPP2R5C in airway remodeling. Additionally, we assessed the effect of lincR-PPP2R5C deficiency on PP2A activity, transforming growth factor (TGF)-β1 signaling, and subsequent EMT in airway epithelial cells.

    MATERIALS AND METHODS

    Mice and establishment of chronic allergy model

    Female lincR-PPP2R5C−/− mice (6–8–week-old, 18–22 g) on a C57BL/J background (Cyagen Biosciences, Suzhou, China) and their age/sex-matched wild-type (WT) controls were housed in the Laboratory Animal Center, Nanjing Medical University (Nanjing, China). LincR-PPP2R5C−/− mice were generated using the CRISPR-Cas9 technology.8 Mice were randomly divided into four groups, including phosphate-buffered saline (PBS)-WT, PBS-LincR-PPP2R5C−/−, house dust mite (HDM)-WT, and HDM-LincR-PPP2R5C−/−. All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of Nanjing Medical University (approval number: IACUC-20170911) and conducted according to the guidelines and regulations.

    Measurement of airway hyperresponsiveness

    Airway hyperresponsiveness was assessed 24 hours after the final challenge using a flexiVent (SCIREQ, Montreal, Canada). Mice were anesthetized by intraperitoneal injection of sodium pentobarbital. The trachea was cannulated, and then mice were administered a baseline dose, followed by increasing doses (6.25, 12.5, 25, and 50 mg/mL) of nebulized acetylcholine (A6625; Sigma-Aldrich, St. Louis, MO, USA) for 3 min, and pulmonary resistance was recorded.

    Collection of serum and bronchoalveolar lavage fluid (BALF)

    Mice were sacrificed by cervical dislocation after measuring airway hyperreactivity. Subsequently, whole blood was collected and centrifuged at 2,000 ×g for 10 minutes to obtain serum. BALF was collected by lung lavages thrice with 0.5 mL PBS containing 1 mM ethylenediaminetetraacetic acid (EDTA). BALF was centrifuged at 500 ×g for 5 minutes at 4°C, and cell pellets were resuspended for counting cells using a hemocytometer (ADVIA2120i; SIEMENS, Munich, Germany).

    Enzyme-linked immunosorbent assay (ELISA)

    ELISA kits were used to determine the concentrations of total immunoglobulin E (432401; BioLegend, San Diego, CA, USA) in serum, and interleukin (IL)-4 (431104; BioLegend), IL-5 (431204; BioLegend), IL-13 (900-K207; PeproTech, Rocky Hill, CT, USA), IL-17A (432504; BioLegend), TGF-β1 (88-8350-88; Thermo Fisher Scientific, Waltham, MA, USA), and collagen I (E-EL-M0325c; Elabscience, Wuhan, China) in supernatants of lung homogenates. ELISA was performed according to the manufacturer’s instructions.

    Histological staining

    After collecting BALF, mouse lungs were perfused by injecting 10 mL ice-cold PBS into the right ventricle. Isolated lung tissues were fixed using 4% paraformaldehyde (G1101; Servicebio, Wuhan, China), embedded in paraffin, and cut into 5-μm sections. Sections were stained with hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), or Sirius Red. Images were obtained using a microscope (BX-53; Olympus Optical, Tokyo, Japan).

    Cell culture

    Mouse lung epithelial cell line MLE-12 (ATCC, Manassas, VA, USA) and human lung epithelial cell line BEAS-2B (Procell Life Science &Technology Co. Ltd., Hubei, China) were cultured in Dulbecco's modified Eagle’s medium containing 10% fetal bovine serum and 1% penicillin/streptomycin at 37°C in an incubator with 5% CO2. Cells were seeded in 24-well plates at intervals of 12 hours and then treated with HDM extract and Alternaria alternata extract (Greer Laboratories, Lenoir, NC, USA). Primary alveolar epithelial cells were isolated as previously described.9 The cells were treated with DT-061 (S8774; Selleck, Princeton, NJ, USA) and Okadaic acid (O9381; Sigma-Aldrich) before HDM and collected for subsequent experiments.

    Western blotting

    Total proteins extracted from tissues and cells were separated using 10%–15% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to polyvinylidene difluoride membranes (Millipore, Billerica, MA, USA). Membranes were blocked with 5% skim milk for 1 hour at room temperature (22°C) and then incubated overnight at 4°C with primary antibodies (Table) at the recommended dilutions. Immunoreactive bands were visualized using a G: Box gel doc system (Syngene, Cambridge, UK) after incubation with peroxidase-conjugated goat anti-rabbit horseradish peroxidase (HRP) immunoglobulin G (IgG) (EarthOx Life Sciences, Burlingame, CA, USA) or goat anti-mouse HRP IgG (EarthOx Life Sciences). The images were analyzed using ImageJ software.

    Table
    Primary antibodies in the study

    PP2A immunoprecipitation phosphatase assay

    The phosphatase activity of PP2A was measured using a commercial PP2A immunoprecipitation phosphatase assay kit (Millipore) according to the manufacturer’s instructions.

    Statistical analysis

    All statistical analyses were conducted using GraphPad Prism v.8 (GraphPad Software, La Jolla, CA, USA). Data are presented as the mean ± standard error. Two-group comparisons were performed using Student’s t-test (2-tailed). One-way analysis of variance (ANOVA) with Tukey’s multiple comparison test was used to compare multiple groups.

    RESULTS

    LincR-PPP2R5C deficiency mitigated airway inflammation

    We treated WT or lincR-PPP2R5C knockout (KO) mice with HDM for 5 weeks (Fig. 1A). This model has previously been described as having sufficient length to allow for changes in the airway structure.10 LincR-PPP2R5C deficiency reduced lung resistance (Fig. 1B). Meanwhile, lincR-PPP2R5C KO reduced total IgE levels in HDM-treated mice (Fig. 1C). Compared to that of WT mice treated with HDM, the number of total cells and eosinophils in BALF decreased in the linR-PPP2R5C KO asthma group (Fig. 1D-H). H&E and PAS staining (Fig. 1I and J) indicated that the HDM-WT group presented high inflammatory cell infiltration and mucus secretion and that lincR-PPP2R5C ablation attenuated allergic inflammation and inhibited mucus secretion. Airway inflammation is typically accompanied by the release of type 2 cytokines.2 LincR-PPP2R5C deficiency decreased the levels of IL-4 and IL-13 (Fig. 1K-N). These data suggested that lincR-PPP2R5C deficiency attenuated airway inflammation in an HDM-induced model of chronic allergic asthma.

    Fig. 1
    Ablation of lincR-PPP2R5C attenuated the airway inflammatory response.
    HDM, house dust mite; PBS, phosphate-buffered saline; WT, wild-type; IL, interleukin; ns, not significant.

    Statistical significance was defined as follows: *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

    LincR-PPP2R5C deficiency reduced airway remodeling

    Next, we assessed whether lincR-PPP2R5C affects airway remodeling. After 5 weeks of HDM exposure, mice showed a phenotype of airway remodeling, as indicated by Sirius red staining, and the number of collagen fibers increased in HDM-treated mice compared to that in the control group. In contrast, lincR-PPP2R5C depletion decreased collagen deposition (Fig. 2A). Similarly, collagen I level decreased in lung tissues of HDM-treated lincR-PPP2R5C KO mice compared to that in HDM-treated WT mice (Fig. 2B). IL-33 can induce collagen release from airway fibroblasts cultured from patients with asthma and contribute to airway remodeling in asthma.11 IL-33 expression in lung tissues of allergic lincR-PPP2R5C KO mice was lower than that in allergic WT mice (Fig. 2C). We further examined the expression of the epithelial marker E-cadherin and the mesenchymal markers N-cadherin and vimentin in lung tissues to assess whether the inhibition of lincR-PPP2R5C deficiency on airway remodeling is owing to EMT inhibition. Notably, HDM extract significantly decreased E-cadherin expression but increased N-cadherin and vimentin expression in WT mice, and these effects were attenuated in HDM-treated lincR-PPP2R5C KO mice (Fig. 2D and E). In summary, lincR-PPP2R5C ablation reduced airway remodeling during chronic asthma.

    Fig. 2
    LincR-PPP2R5C ablation alleviated HDM-induced airway remodeling in mice.
    WT, wild-type; PBS, phosphate-buffered saline; HDM, house dust mite; IL, interleukin.

    Statistical significance was defined as follows: *P < 0.05; **P < 0.01; ***P < 0.001.

    LincR-PPP2R5C deficiency alleviated allergen-induced EMT in vitro

    Allergens are related to the pathogenesis of asthma, and these factors are known to induce barrier dysfunction and EMT in epithelial cells.12 HDM and A. alternata extracts decreased E-cadherin expression and increased the level of alpha-smooth muscle actin in MLE-12 cells (Fig. 3A and B). Furthermore, to explore the roles of lincR-PPP2R5C in HDM-induced EMT, we isolated primary alveolar epithelial cells and treated them with HDM. Like our in vivo observations, E-cadherin expression decreased, whereas N-cadherin and vimentin expression increased in the HDM-treated groups (Fig. 3C and D). E-cadherin levels in lincR-PPP2R5C-deficient alveolar epithelial cells treated with HDM were higher than those in HDM-treated WT cells, whereas N-cadherin and vimentin levels were significantly low. Taken together, lincR-PPP2R5C deficiency directly alleviated EMT induced by allergens in vitro.

    Fig. 3
    LincR-PPP2R5C deficiency alleviated allergen-induced EMT in epithelial cells.
    α-SMA, α-smooth muscle actin; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HDM, house dust mite; PBS, phosphate-buffered saline; HDM, house dust mite; WT, wild-type.

    Statistical significance was defined as follows: *P < 0.05; **P < 0.01; ***P < 0.001.

    Ablated EMT in lincR-PPP2R5C-defective epithelial cells was associated with TGF-β1

    TGF-β1 plays an important role in many chronic diseases, especially airway remodeling and fibrosis.13 HDM can cause TGF-β1 release, promoting airway remodeling via EMT.14 Here, HDM treatment increased TGF-β1 levels in MLE-12 cells (Fig. 4A). We therefore examined the effects of lincR-PPP2R5C on HDM-induced activation of TGF-β1 signaling and compared TGF-β1 levels in primary alveolar epithelial cells isolated from different groups of mice. Our results indicated that TGF-β1 levels were reduced by HDM treatment in lincR-PPP2R5C KO mice compared to that in the WT group (Fig. 4B). Furthermore, we investigated TGF-β1 expression in a chronic allergic airway model and found that lincR-PPP2R5C deficiency in HDM-treated mice significantly decreased TGF-β1 levels (Fig. 4C and D). Taken together, these results suggested that the mechanism of EMT through lincR-PPP2R5C might be associated with TGF-β1.

    Fig. 4
    Ablated EMT in lincR-PPP2R5C-defective epithelial cells was associated with TGF-β1.
    TGF, transforming growth factor; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; PBS, phosphate-buffered saline; HDM, house dust mite; WT, wild-type.

    Statistical significance was defined as follows: *P < 0.05; **P < 0.01; ***P < 0.001.

    LincR-PPP2R5C targeted PP2A in regulating TGF-β1 production in epithelial cells

    We have previously demonstrated a role for lincR-PPP2R5C and its downstream signaling pathways in the induction of allergic disease in acute ovalbumin (OVA)-driven mouse model. LincR-PPP2R5C deficiency alleviated Th2-driven airway inflammation, which was associated with PP2A activity.8 To explore whether PP2A holoenzymes are responsible for the differences between WT and LincR-PPP2R5C KO allergic mice, the phosphatase activity of PP2A was measured. PP2A activity was higher in allergic lincR-PPP2R5C KO mice than in allergic WT mice (Fig. 5A). PP2A activity is enhanced by the methylation of the C-terminal Leu309 residue in its catalytic center.15 Accordingly, we determined the methylation levels of PP2A in lung tissues. PP2A methylation increased following HDM treatment in lincR-PPP2R5C KO mice compared to that in WT mice (Fig. 5B). To determine whether PP2A activity indeed plays a critical role in lincR-PPP2R5C-mediated EMT, we exogenously treated 2 epithelial cell lines (MLE-12 and BEAS-2B) with OA, a PP2A inhibitor,16 and DT-061, a PP2A-selective agonist.17 As shown in Fig. 5C and D, TGF-β1 level increased by HDM treatment and decreased after addition of DT-061 that activated PP2A and alleviated EMT. Moreover, relatively low levels of N-cadherin and Snail were observed. In contrast, the TGF-β1 level of HDM-treated group was still higher than that of the control group, and upon the addition of OA, the TGF-β1 level was enhanced and resulted in EMT (Fig. 5E and F). Similar results were obtained with primary cells. DT-061 attenuated TGF-β1 level in mouse primary alveolar epithelial cells (Fig. 5G). Finally, we isolated primary alveolar epithelial cells from WT and lincR-PPP2R5C KO mice and administered OA prior to HDM administration (Fig. 5H). LincR-PPP2R5C ablation decreased the TGF-β1 level, which was reversed by adding OA. Taken together, lincR-PPP2R5C deficiency increased PP2A activity, leading to decreased TGF-β1 expression and reduced EMT.

    Fig. 5
    LincR-PPP2R5C targeted PP2A and PP2A-mediated TGF-β1 production in epithelial cells.
    PP2A, protein phosphatase 2A; WT, wild-type; PBS, phosphate-buffered saline; HDM, house dust mite; TGF, transforming growth factor; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; DMSO, dimethyl sulfoxide; EtOH, ethanol; OA, okadaic acid; ns, not significant.

    Statistical significance was defined as follows: *P < 0.05; **P < 0.01.

    DISCUSSION

    The present study indicated that lincR-PPP2R5C deficiency alleviated airway remodeling. Specifically, the PP2A and TGF-β1 signaling pathways were suppressed in allergic lincR-PPP2R5C KO mice, leading to the downregulation of EMT. Previous studies have identified that allergic asthma is induced by allergens such as house dust mites, which are recognized by Th2 cells, releasing type 2 cytokines (IL-4, IL-5, IL-9, and IL-13).2, 3 HDM activates the TGF-β1 pathway during airway remodeling.18 Indeed, Chakir et al. 19 found TGF-β1 levels are significantly higher in patients with asthma than in control subjects, which do not decrease after treatment with oral corticosteroids. EMT has been reported to be involved in the pathological process of airway remodeling in asthma.18, 20, 21 Importantly, we have previously demonstrated a lncRNA named lincR-PPP2R5C and its role in an acute OVA-driven mouse model. In the acute setting, lincR-PPP2R5C deficiency was sufficient to alleviate Th2-driven airway inflammation.8 Therefore, we investigated whether lincR-PPP2R5C deficiency exerted an anti-EMT effect by inactivating TGF-β1 signaling. We found that lincR-PPP2R5C KO attenuated HDM-induced TGF-β1 levels in vivo and in vitro. Therefore, ablation of lincR-PPP2R5C alleviated HDM-induced airway remodeling by inhibiting EMT through TGF-β1 signaling.

    PP2A is the most abundant serine/threonine phosphatase in mammals.22 Xing et al. 15 revealed that the methylation at leucine-309 residue of catalytic C-subunit (PP2Ac) is the main modification modulating PP2A activity, and its activity is reduced in asthma.23 Restoration of PP2A expression in A549 cells inhibits transglutaminase-2-dependent N-cadherin expression during TGF-β1-induced EMT.24 Consistent with these observations, our results revealed that PP2A activity was higher in allergic lincR-PPP2R5C KO mice than in allergic WT mice, while TGF-β1 level was relatively low. Moreover, results with the PP2A inhibitor and PP2A-selective agonist showed that the enhanced activity of PP2A decreased TGF-β1 expression. Together, our data suggest that modulating lincR-PPP2R5C and its downstream PP2A/TGF-β1 signaling pathway affects airway remodeling. LncRNAs, i.e., lincR-PPP2R5C, may be potential candidates in the therapy of airway remodeling in allergic asthma.

    Notes

    Disclosure:There are no financial or other issues that might lead to a conflict of interest.

    ACKNOWLEDGMENTS

    This study was supported by the Precision Medicine Research of the National Key Research and Development Plan of China (2016YFC0905800), the National Natural Science Foundation of China (81970031, 81770031, and 82171738), and the Natural Science Foundation of Jiangsu Province (BK20171501, BK2017080, and BK20181497).

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    Publication Types
    Brief Communication
    MeSH Terms
    Airway Remodeling*
    Animals
    Asthma*
    Epithelial-Mesenchymal Transition*
    Epithelial Cells
    Lung
    Mice
    Phosphoprotein Phosphatases
    Protein Phosphatase 2
    Pyroglyphidae
    RNA, Long Noncoding
    Transforming Growth Factors
    Metrics
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