Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-β/Smad2/3 pathway intensification and antifibrotic TGF-β/Smad1/5/(8)9 pathway impairment
Abstract Airway remodelling with subepithelial fibrosis, which abolishes the physiological functions of the bronchial wall, is a major issue in bronchial asthma. Human bronchial fibroblasts (HBFs) derived from patients diagnosed with asthma display in vitro predestination towards TGF-β1-induced fibr...
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| Format: | Article |
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Nature Portfolio
2020-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-020-73473-7 |
| _version_ | 1831633547151015936 |
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| author | Dawid Wnuk Milena Paw Karolina Ryczek Grażyna Bochenek Krzysztof Sładek Zbigniew Madeja Marta Michalik |
| author_facet | Dawid Wnuk Milena Paw Karolina Ryczek Grażyna Bochenek Krzysztof Sładek Zbigniew Madeja Marta Michalik |
| author_sort | Dawid Wnuk |
| collection | DOAJ |
| description | Abstract Airway remodelling with subepithelial fibrosis, which abolishes the physiological functions of the bronchial wall, is a major issue in bronchial asthma. Human bronchial fibroblasts (HBFs) derived from patients diagnosed with asthma display in vitro predestination towards TGF-β1-induced fibroblast-to-myofibroblast transition (FMT), a key event in subepithelial fibrosis. As commonly used anti-asthmatic drugs do not reverse the structural changes of the airways, and the molecular mechanism of enhanced asthma-related TGF-β1-induced FMT is poorly understood, we investigated the balance between the profibrotic TGF-β/Smad2/3 and the antifibrotic TGF-β/Smad1/5/9 signalling pathways and its role in the myofibroblast formation of HBF populations derived from asthmatic and non-asthmatic donors. Our findings showed for the first time that TGF-β-induced activation of the profibrotic Smad2/3 signalling pathway was enhanced, but the activation of the antifibrotic Smad1/5/(8)9 pathway by TGF-β1 was significantly diminished in fibroblasts from asthmatic donors compared to those from their healthy counterparts. The impairment of the antifibrotic TGF-β/Smad1/5/(8)9 pathway in HBFs derived from asthmatic donors was correlated with enhanced FMT. Furthermore, we showed that Smad1 silencing in HBFs from non-asthmatic donors increased the FMT potential in these cells. Additionally, we demonstrated that activation of antifibrotic Smad signalling via BMP7 or isoliquiritigenin [a small-molecule activator of the TGF-β/Smad1/5/(8)9 pathway] administration prevents FMT in HBFs from asthmatic donors through downregulation of profibrotic genes, e.g., α-SMA and fibronectin. Our data suggest that influencing the balance between the antifibrotic and profibrotic TGF-β/Smad signalling pathways using BMP7-mimetic compounds presents an unprecedented opportunity to inhibit subepithelial fibrosis during airway remodelling in asthma. |
| first_indexed | 2024-12-19T05:38:08Z |
| format | Article |
| id | doaj.art-4e8d04ff46cd4efcaa6314b15934e936 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T05:38:08Z |
| publishDate | 2020-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
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| spelling | doaj.art-4e8d04ff46cd4efcaa6314b15934e9362022-12-21T20:34:04ZengNature PortfolioScientific Reports2045-23222020-10-0110111610.1038/s41598-020-73473-7Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-β/Smad2/3 pathway intensification and antifibrotic TGF-β/Smad1/5/(8)9 pathway impairmentDawid Wnuk0Milena Paw1Karolina Ryczek2Grażyna Bochenek3Krzysztof Sładek4Zbigniew Madeja5Marta Michalik6Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian UniversityDepartment of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian UniversityDepartment of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian UniversityDepartment of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical CollegeDepartment of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical CollegeDepartment of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian UniversityDepartment of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian UniversityAbstract Airway remodelling with subepithelial fibrosis, which abolishes the physiological functions of the bronchial wall, is a major issue in bronchial asthma. Human bronchial fibroblasts (HBFs) derived from patients diagnosed with asthma display in vitro predestination towards TGF-β1-induced fibroblast-to-myofibroblast transition (FMT), a key event in subepithelial fibrosis. As commonly used anti-asthmatic drugs do not reverse the structural changes of the airways, and the molecular mechanism of enhanced asthma-related TGF-β1-induced FMT is poorly understood, we investigated the balance between the profibrotic TGF-β/Smad2/3 and the antifibrotic TGF-β/Smad1/5/9 signalling pathways and its role in the myofibroblast formation of HBF populations derived from asthmatic and non-asthmatic donors. Our findings showed for the first time that TGF-β-induced activation of the profibrotic Smad2/3 signalling pathway was enhanced, but the activation of the antifibrotic Smad1/5/(8)9 pathway by TGF-β1 was significantly diminished in fibroblasts from asthmatic donors compared to those from their healthy counterparts. The impairment of the antifibrotic TGF-β/Smad1/5/(8)9 pathway in HBFs derived from asthmatic donors was correlated with enhanced FMT. Furthermore, we showed that Smad1 silencing in HBFs from non-asthmatic donors increased the FMT potential in these cells. Additionally, we demonstrated that activation of antifibrotic Smad signalling via BMP7 or isoliquiritigenin [a small-molecule activator of the TGF-β/Smad1/5/(8)9 pathway] administration prevents FMT in HBFs from asthmatic donors through downregulation of profibrotic genes, e.g., α-SMA and fibronectin. Our data suggest that influencing the balance between the antifibrotic and profibrotic TGF-β/Smad signalling pathways using BMP7-mimetic compounds presents an unprecedented opportunity to inhibit subepithelial fibrosis during airway remodelling in asthma.https://doi.org/10.1038/s41598-020-73473-7 |
| spellingShingle | Dawid Wnuk Milena Paw Karolina Ryczek Grażyna Bochenek Krzysztof Sładek Zbigniew Madeja Marta Michalik Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-β/Smad2/3 pathway intensification and antifibrotic TGF-β/Smad1/5/(8)9 pathway impairment Scientific Reports |
| title | Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-β/Smad2/3 pathway intensification and antifibrotic TGF-β/Smad1/5/(8)9 pathway impairment |
| title_full | Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-β/Smad2/3 pathway intensification and antifibrotic TGF-β/Smad1/5/(8)9 pathway impairment |
| title_fullStr | Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-β/Smad2/3 pathway intensification and antifibrotic TGF-β/Smad1/5/(8)9 pathway impairment |
| title_full_unstemmed | Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-β/Smad2/3 pathway intensification and antifibrotic TGF-β/Smad1/5/(8)9 pathway impairment |
| title_short | Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-β/Smad2/3 pathway intensification and antifibrotic TGF-β/Smad1/5/(8)9 pathway impairment |
| title_sort | enhanced asthma related fibroblast to myofibroblast transition is the result of profibrotic tgf β smad2 3 pathway intensification and antifibrotic tgf β smad1 5 8 9 pathway impairment |
| url | https://doi.org/10.1038/s41598-020-73473-7 |
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