The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects
Abstract Small airway remodeling (SAR) is a key phenomenon of airflow obstruction in smokers, leading to chronic obstructive pulmonary disease (COPD). SAR results in an increased thickness of small airway walls, with a combination of peribronchiolar fibrosis with increased fibrous tissue and accumul...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-25993-7 |
| _version_ | 1797945970473828352 |
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| author | Arnaud Jean Florent Tiendrébéogo Thibaud Soumagne François Pellegrin Maylis Dagouassat Jeanne Tran Van Nhieu Philippe Caramelle Emmanuel N. Paul Benjamin Even Maeva Zysman Yvon Julé Abdoulaye Samb Jorge Boczkowski Sophie Lanone Frédéric Schlemmer |
| author_facet | Arnaud Jean Florent Tiendrébéogo Thibaud Soumagne François Pellegrin Maylis Dagouassat Jeanne Tran Van Nhieu Philippe Caramelle Emmanuel N. Paul Benjamin Even Maeva Zysman Yvon Julé Abdoulaye Samb Jorge Boczkowski Sophie Lanone Frédéric Schlemmer |
| author_sort | Arnaud Jean Florent Tiendrébéogo |
| collection | DOAJ |
| description | Abstract Small airway remodeling (SAR) is a key phenomenon of airflow obstruction in smokers, leading to chronic obstructive pulmonary disease (COPD). SAR results in an increased thickness of small airway walls, with a combination of peribronchiolar fibrosis with increased fibrous tissue and accumulation of mesenchymal and epithelial cells. SAR pathogenesis is still unclear but recent data suggest that alterations in telomerase activity could represent a possible underlying mechanism of SAR. Our study was dedicated to identify a potential protective role of TA-65, a pharmacological telomerase activator, in a cigarette smoke (CS) model of SAR in mice, and to further precise if extra-telomeric effects of telomerase, involving oxidative stress modulation, could explain it. C57BL/6J mice were daily exposed to air or CS during 4 weeks with or without a concomitant administration of TA-65 starting 7 days before CS exposure. Morphological analyses were performed, and mucus production, myofibroblast differentiation, collagen deposition, as well as transforming growth factor-β1 (TGF-β1) expression in the small airway walls were examined. In addition, the effects of TA-65 treatment on TGF-β expression, fibroblast-to-myofibroblast differentiation, reactive oxygen species (ROS) production and catalase expression and activity were evaluated in primary cultures of pulmonary fibroblasts and/or mouse embryonic fibroblasts in vitro. Exposure to CS during 4 weeks induced SAR in mice, characterized by small airway walls thickening and peribronchiolar fibrosis (increased deposition of collagen, expression of α-SMA in small airway walls), without mucus overproduction. Treatment of mice with TA-65 protected them from CS-induced SAR. This effect was associated with the prevention of CS-induced TGF-β expression in vivo, the blockade of TGF-β-induced myofibroblast differentiation, and the reduction of TGF-β-induced ROS production that correlates with an increase of catalase expression and activity. Our findings demonstrate that telomerase is a critical player of SAR, probably through extra-telomeric anti-oxidant effects, and therefore provide new insights in the understanding and treatment of COPD pathogenesis. |
| first_indexed | 2024-04-10T21:03:28Z |
| format | Article |
| id | doaj.art-b4ce8bce8ecb4953b4a855f5a38742ba |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-10T21:03:28Z |
| publishDate | 2023-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-b4ce8bce8ecb4953b4a855f5a38742ba2023-01-22T12:10:06ZengNature PortfolioScientific Reports2045-23222023-01-0113111110.1038/s41598-022-25993-7The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effectsArnaud Jean Florent Tiendrébéogo0Thibaud Soumagne1François Pellegrin2Maylis Dagouassat3Jeanne Tran Van Nhieu4Philippe Caramelle5Emmanuel N. Paul6Benjamin Even7Maeva Zysman8Yvon Julé9Abdoulaye Samb10Jorge Boczkowski11Sophie Lanone12Frédéric Schlemmer13IMRB, INSERM U955IMRB, INSERM U955IMRB, INSERM U955IMRB, INSERM U955IMRB, INSERM U955IMRB, INSERM U955IMRB, INSERM U955IMRB, INSERM U955IMRB, INSERM U955BioCellviaLaboratoire de physiologie et d’explorations fonctionnelles physiologiques, Université Cheik Anta DiopIMRB, INSERM U955IMRB, INSERM U955IMRB, INSERM U955Abstract Small airway remodeling (SAR) is a key phenomenon of airflow obstruction in smokers, leading to chronic obstructive pulmonary disease (COPD). SAR results in an increased thickness of small airway walls, with a combination of peribronchiolar fibrosis with increased fibrous tissue and accumulation of mesenchymal and epithelial cells. SAR pathogenesis is still unclear but recent data suggest that alterations in telomerase activity could represent a possible underlying mechanism of SAR. Our study was dedicated to identify a potential protective role of TA-65, a pharmacological telomerase activator, in a cigarette smoke (CS) model of SAR in mice, and to further precise if extra-telomeric effects of telomerase, involving oxidative stress modulation, could explain it. C57BL/6J mice were daily exposed to air or CS during 4 weeks with or without a concomitant administration of TA-65 starting 7 days before CS exposure. Morphological analyses were performed, and mucus production, myofibroblast differentiation, collagen deposition, as well as transforming growth factor-β1 (TGF-β1) expression in the small airway walls were examined. In addition, the effects of TA-65 treatment on TGF-β expression, fibroblast-to-myofibroblast differentiation, reactive oxygen species (ROS) production and catalase expression and activity were evaluated in primary cultures of pulmonary fibroblasts and/or mouse embryonic fibroblasts in vitro. Exposure to CS during 4 weeks induced SAR in mice, characterized by small airway walls thickening and peribronchiolar fibrosis (increased deposition of collagen, expression of α-SMA in small airway walls), without mucus overproduction. Treatment of mice with TA-65 protected them from CS-induced SAR. This effect was associated with the prevention of CS-induced TGF-β expression in vivo, the blockade of TGF-β-induced myofibroblast differentiation, and the reduction of TGF-β-induced ROS production that correlates with an increase of catalase expression and activity. Our findings demonstrate that telomerase is a critical player of SAR, probably through extra-telomeric anti-oxidant effects, and therefore provide new insights in the understanding and treatment of COPD pathogenesis.https://doi.org/10.1038/s41598-022-25993-7 |
| spellingShingle | Arnaud Jean Florent Tiendrébéogo Thibaud Soumagne François Pellegrin Maylis Dagouassat Jeanne Tran Van Nhieu Philippe Caramelle Emmanuel N. Paul Benjamin Even Maeva Zysman Yvon Julé Abdoulaye Samb Jorge Boczkowski Sophie Lanone Frédéric Schlemmer The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects Scientific Reports |
| title | The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects |
| title_full | The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects |
| title_fullStr | The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects |
| title_full_unstemmed | The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects |
| title_short | The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects |
| title_sort | telomerase activator ta 65 protects from cigarette smoke induced small airway remodeling in mice through extra telomeric effects |
| url | https://doi.org/10.1038/s41598-022-25993-7 |
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