Jan Christoph Thomassen, Christina Vohlen, Ernst Rietschel, Miguel A Alejandre Alcazar, Silke van Koningsbruggen-Rietschel
{"title":"人支气管上皮细胞中Elafin的表达受cftr -突变和tgf - β1的调控。","authors":"Jan Christoph Thomassen, Christina Vohlen, Ernst Rietschel, Miguel A Alejandre Alcazar, Silke van Koningsbruggen-Rietschel","doi":"10.1016/j.jcf.2025.08.016","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Cystic Fibrosis (CF) lung disease is characterized by inflammation and progressive matrix remodeling. These processes are influenced by genetic modifiers such as Transforming Growth Factor β<sub>1</sub>, (TGFβ<sub>1)</sub> which is enhanced by an imbalance of proteases, e.g. neutrophile elastase (NE) and its inhibitor elafin. Elevated TGFβ<sub>1</sub> concentrations in sputum are linked to impaired lung function in people with CF (pwCF); and decreased elafin levels in sputum are associated with P. aeruginosa infection. The direct influence of CFTR-mutations and the impact of TGFβ<sub>1</sub> on the expression of elafin has not yet been examined. Therefore, we investigated (1) the direct impact of the CFTR-mutation itself on elafin expression, (2) the interaction of TGFβ<sub>1</sub> and CFTR-mutation on elafin expression, and (3) the effect of inhibiting TGFβ<sub>1</sub> on the expression of elafin in human bronchial epithelial cells (HBE).</p><p><strong>Methods: </strong>(1) Gene expression of elafin was measured by qRT-PCR and ELISA in CFTR-diseased (delF508 homozygous; CF-DHBE) and wildtype HBE cells (NHBE). (2) CF-DHBE and NHBE were stimulated with TGFβ<sub>1</sub> or vehicle and finally (3) TGFβ<sub>1</sub> was inhibited by Pirfenidone/SB43. Gene expression of elafin and inflammatory mediators, as well as inhibitors of proteases were analyzed by qRT-PCR or immunoblot.</p><p><strong>Results: </strong>(1) mRNA and protein expression of elafin is significantly reduced in CFTR-mutated HBE when compared to NHBE cells. (2) Furthermore, the expression of elafin is inhibited by the genetic modifier TGFβ<sub>1</sub>. (3) Inhibition of TGFβ<sub>1</sub> induced elafin expression in CF-DHBE cells and abrogated the CFTR- TGFβ<sub>1</sub> mediated inhibitory effect in HBE.</p><p><strong>Conclusions: </strong>Our study shows that CFTR-mutation itself mediates effects on the homeostasis of proteases by reducing the expression of elafin. Furthermore, the exposure to high TGFβ<sub>1</sub> concentrations increases the CFTR-mutation mediated reduction of elafin expression. Restoring elafin levels and/or inhibiting TGFβ<sub>1</sub> might be possible therapeutic options to reduce pulmonary inflammation and remodelling in CF.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":6.0000,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Elafin expression is regulated by CFTR-mutation and TGFβ<sub>1</sub> in human bronchial epithelial cells.\",\"authors\":\"Jan Christoph Thomassen, Christina Vohlen, Ernst Rietschel, Miguel A Alejandre Alcazar, Silke van Koningsbruggen-Rietschel\",\"doi\":\"10.1016/j.jcf.2025.08.016\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Cystic Fibrosis (CF) lung disease is characterized by inflammation and progressive matrix remodeling. These processes are influenced by genetic modifiers such as Transforming Growth Factor β<sub>1</sub>, (TGFβ<sub>1)</sub> which is enhanced by an imbalance of proteases, e.g. neutrophile elastase (NE) and its inhibitor elafin. Elevated TGFβ<sub>1</sub> concentrations in sputum are linked to impaired lung function in people with CF (pwCF); and decreased elafin levels in sputum are associated with P. aeruginosa infection. The direct influence of CFTR-mutations and the impact of TGFβ<sub>1</sub> on the expression of elafin has not yet been examined. Therefore, we investigated (1) the direct impact of the CFTR-mutation itself on elafin expression, (2) the interaction of TGFβ<sub>1</sub> and CFTR-mutation on elafin expression, and (3) the effect of inhibiting TGFβ<sub>1</sub> on the expression of elafin in human bronchial epithelial cells (HBE).</p><p><strong>Methods: </strong>(1) Gene expression of elafin was measured by qRT-PCR and ELISA in CFTR-diseased (delF508 homozygous; CF-DHBE) and wildtype HBE cells (NHBE). (2) CF-DHBE and NHBE were stimulated with TGFβ<sub>1</sub> or vehicle and finally (3) TGFβ<sub>1</sub> was inhibited by Pirfenidone/SB43. Gene expression of elafin and inflammatory mediators, as well as inhibitors of proteases were analyzed by qRT-PCR or immunoblot.</p><p><strong>Results: </strong>(1) mRNA and protein expression of elafin is significantly reduced in CFTR-mutated HBE when compared to NHBE cells. (2) Furthermore, the expression of elafin is inhibited by the genetic modifier TGFβ<sub>1</sub>. (3) Inhibition of TGFβ<sub>1</sub> induced elafin expression in CF-DHBE cells and abrogated the CFTR- TGFβ<sub>1</sub> mediated inhibitory effect in HBE.</p><p><strong>Conclusions: </strong>Our study shows that CFTR-mutation itself mediates effects on the homeostasis of proteases by reducing the expression of elafin. Furthermore, the exposure to high TGFβ<sub>1</sub> concentrations increases the CFTR-mutation mediated reduction of elafin expression. Restoring elafin levels and/or inhibiting TGFβ<sub>1</sub> might be possible therapeutic options to reduce pulmonary inflammation and remodelling in CF.</p>\",\"PeriodicalId\":15452,\"journal\":{\"name\":\"Journal of Cystic Fibrosis\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2025-09-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Cystic Fibrosis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jcf.2025.08.016\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RESPIRATORY SYSTEM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Cystic Fibrosis","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jcf.2025.08.016","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RESPIRATORY SYSTEM","Score":null,"Total":0}
Elafin expression is regulated by CFTR-mutation and TGFβ1 in human bronchial epithelial cells.
Background: Cystic Fibrosis (CF) lung disease is characterized by inflammation and progressive matrix remodeling. These processes are influenced by genetic modifiers such as Transforming Growth Factor β1, (TGFβ1) which is enhanced by an imbalance of proteases, e.g. neutrophile elastase (NE) and its inhibitor elafin. Elevated TGFβ1 concentrations in sputum are linked to impaired lung function in people with CF (pwCF); and decreased elafin levels in sputum are associated with P. aeruginosa infection. The direct influence of CFTR-mutations and the impact of TGFβ1 on the expression of elafin has not yet been examined. Therefore, we investigated (1) the direct impact of the CFTR-mutation itself on elafin expression, (2) the interaction of TGFβ1 and CFTR-mutation on elafin expression, and (3) the effect of inhibiting TGFβ1 on the expression of elafin in human bronchial epithelial cells (HBE).
Methods: (1) Gene expression of elafin was measured by qRT-PCR and ELISA in CFTR-diseased (delF508 homozygous; CF-DHBE) and wildtype HBE cells (NHBE). (2) CF-DHBE and NHBE were stimulated with TGFβ1 or vehicle and finally (3) TGFβ1 was inhibited by Pirfenidone/SB43. Gene expression of elafin and inflammatory mediators, as well as inhibitors of proteases were analyzed by qRT-PCR or immunoblot.
Results: (1) mRNA and protein expression of elafin is significantly reduced in CFTR-mutated HBE when compared to NHBE cells. (2) Furthermore, the expression of elafin is inhibited by the genetic modifier TGFβ1. (3) Inhibition of TGFβ1 induced elafin expression in CF-DHBE cells and abrogated the CFTR- TGFβ1 mediated inhibitory effect in HBE.
Conclusions: Our study shows that CFTR-mutation itself mediates effects on the homeostasis of proteases by reducing the expression of elafin. Furthermore, the exposure to high TGFβ1 concentrations increases the CFTR-mutation mediated reduction of elafin expression. Restoring elafin levels and/or inhibiting TGFβ1 might be possible therapeutic options to reduce pulmonary inflammation and remodelling in CF.
期刊介绍：
The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.
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