{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T15:35:54Z","timestamp":1794497754545,"version":"4.9.1"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,10,5]],"date-time":"2020-10-05T00:00:00Z","timestamp":1601856000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,5]],"date-time":"2020-10-05T00:00:00Z","timestamp":1601856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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-\u03b2\n                    <jats:sub>1<\/jats:sub>\n                    -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-\u03b2\n                    <jats:sub>1<\/jats:sub>\n                    -induced FMT is poorly understood, we investigated the balance between the profibrotic TGF-\u03b2\/Smad2\/3 and the antifibrotic TGF-\u03b2\/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-\u03b2-induced activation of the profibrotic Smad2\/3 signalling pathway was enhanced, but the activation of the antifibrotic Smad1\/5\/(8)9 pathway by TGF-\u03b2\n                    <jats:sub>1<\/jats:sub>\n                    was significantly diminished in fibroblasts from asthmatic donors compared to those from their healthy counterparts. The impairment of the antifibrotic TGF-\u03b2\/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-\u03b2\/Smad1\/5\/(8)9 pathway] administration prevents FMT in HBFs from asthmatic donors through downregulation of profibrotic genes, e.g., \u03b1-SMA and fibronectin. Our data suggest that influencing the balance between the antifibrotic and profibrotic TGF-\u03b2\/Smad signalling pathways using BMP7-mimetic compounds presents an unprecedented opportunity to inhibit subepithelial fibrosis during airway remodelling in asthma.\n                  <\/jats:p>","DOI":"10.1038\/s41598-020-73473-7","type":"journal-article","created":{"date-parts":[[2020,10,5]],"date-time":"2020-10-05T06:05:05Z","timestamp":1601877905000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-\u03b2\/Smad2\/3 pathway intensification and antifibrotic TGF-\u03b2\/Smad1\/5\/(8)9 pathway impairment"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5807-2440","authenticated-orcid":false,"given":"Dawid","family":"Wnuk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3325-7916","authenticated-orcid":false,"given":"Milena","family":"Paw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Ryczek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gra\u017cyna","family":"Bochenek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"S\u0142adek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5523-1215","authenticated-orcid":false,"given":"Zbigniew","family":"Madeja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1482-2959","authenticated-orcid":false,"given":"Marta","family":"Michalik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,5]]},"reference":[{"key":"73473_CR1","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.1056\/NEJMoa1014350","volume":"364","author":"CL Grainge","year":"2011","unstructured":"Grainge, C. L. et al. Effect of bronchoconstriction on airway remodeling in asthma. N. Engl. J. Med. 364, 2006\u20132015 (2011).","journal-title":"N. Engl. J. Med."},{"key":"73473_CR2","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/S1526054202002610","volume":"3","author":"L Baldwin","year":"2002","unstructured":"Baldwin, L. & Roche, W. R. Does remodelling of the airway wall precede asthma?. Paediatr. Respir. Rev. 3, 315\u2013320 (2002).","journal-title":"Paediatr. Respir. Rev."},{"key":"73473_CR3","doi-asserted-by":"publisher","first-page":"e95","DOI":"10.1016\/j.ddmec.2012.11.004","volume":"9","author":"JG Martin","year":"2012","unstructured":"Martin, J. G. & Verma, N. Mechanisms of airway remodeling in asthma. Drug Discov. Today Dis. Mech. 9, e95\u2013e102 (2012).","journal-title":"Drug Discov. Today Dis. Mech."},{"key":"73473_CR4","doi-asserted-by":"publisher","first-page":"3943","DOI":"10.1007\/s00018-018-2899-4","volume":"75","author":"M Michalik","year":"2018","unstructured":"Michalik, M. et al. Fibroblast-to-myofibroblast transition in bronchial asthma. Cell. Mol. Life Sci. 75, 3943\u20133961 (2018).","journal-title":"Cell. Mol. Life Sci."},{"key":"73473_CR5","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1007\/s00441-016-2566-8","volume":"367","author":"H Fehrenbach","year":"2017","unstructured":"Fehrenbach, H., Wagner, C. & Wegmann, M. Airway remodeling in asthma: what really matters. Cell Tissue Res. 367, 551\u2013569 (2017).","journal-title":"Cell Tissue Res."},{"key":"73473_CR6","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1146\/annurev-pathol-020712-163930","volume":"8","author":"JS Duffield","year":"2013","unstructured":"Duffield, J. S., Lupher, M., Thannickal, V. J. & Wynn, T. A. Host responses in tissue repair and fibrosis. Annu. Rev. Pathol. Mech. Dis. 8, 241\u2013276 (2013).","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"73473_CR7","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.2353\/ajpath.2007.070112","volume":"170","author":"B Hinz","year":"2007","unstructured":"Hinz, B. et al. The myofibroblast: one function, multiple origins. Am. J. Pathol. 170, 1807\u20131816 (2007).","journal-title":"Am. J. Pathol."},{"key":"73473_CR8","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1002\/path.4253","volume":"231","author":"R Kramann","year":"2013","unstructured":"Kramann, R., DiRocco, D. P. & Humphreys, B. D. Understanding the origin, activation and regulation of matrix-producing myofibroblasts for treatment of fibrotic disease. J. Pathol. 231, 273\u2013289 (2013).","journal-title":"J. Pathol."},{"key":"73473_CR9","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1172\/JCI93558","volume":"128","author":"SE Di Carlo","year":"2018","unstructured":"Di Carlo, S. E. & Peduto, L. The perivascular origin of pathological fibroblasts. J. Clin. Investig. 128, 54\u201363 (2018).","journal-title":"J. Clin. Investig."},{"key":"73473_CR10","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1007\/s00018-015-2110-0","volume":"73","author":"IA Darby","year":"2016","unstructured":"Darby, I. A., Zakuan, N., Billet, F. & Desmouli\u00e8re, A. The myofibroblast, a key cell in normal and pathological tissue repair. Cell. Mol. Life Sci. 73, 1145\u20131157 (2016).","journal-title":"Cell. Mol. Life Sci."},{"key":"73473_CR11","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.stem.2017.07.011","volume":"21","author":"E El Agha","year":"2017","unstructured":"El Agha, E. et al. Mesenchymal stem cells in fibrotic disease. Cell Stem Cell 21, 166\u2013177 (2017).","journal-title":"Cell Stem Cell"},{"key":"73473_CR12","first-page":"194","volume":"15","author":"M Michalik","year":"2009","unstructured":"Michalik, M. et al. Asthmatic bronchial fibroblasts demonstrate enhanced potential to differentiate into myofibroblasts in culture. Med. Sci. Monit. 15, 194\u2013201 (2009).","journal-title":"Med. Sci. Monit."},{"key":"73473_CR13","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1165\/rcmb.2007-0089OC","volume":"37","author":"H Sugiura","year":"2007","unstructured":"Sugiura, H. et al. Cultured lung fibroblasts from ovalbumin-challenged \u2018asthmatic\u2019 mice differ functionally from normal. Am. J. Respir. Cell Mol. Biol. 37, 424\u2013430 (2007).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"73473_CR14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0116840","author":"M Sarna","year":"2015","unstructured":"Sarna, M. et al. Undifferentiated bronchial fibroblasts derived from asthmatic patients display higher elastic modulus than their non-asthmatic counterparts. PLoS ONE https:\/\/doi.org\/10.1371\/journal.pone.0116840 (2015).","journal-title":"PLoS ONE"},{"key":"73473_CR15","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1016\/j.rmed.2011.04.009","volume":"105","author":"M Michalik","year":"2011","unstructured":"Michalik, M. et al. Transition of asthmatic bronchial fibroblasts to myofibroblasts is inhibited by cell-cell contacts. Respir. Med. 105, 1467\u20131475 (2011).","journal-title":"Respir. Med."},{"key":"73473_CR16","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1165\/rcmb.2015-0255OC","volume":"57","author":"M Paw","year":"2017","unstructured":"Paw, M. et al. Connexin43 controls the myofibroblastic differentiation of bronchial fibroblasts from patients with asthma. Am. J. Respir. Cell Mol. Biol. 57, 100\u2013110 (2017).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"73473_CR17","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.cyto.2017.09.002","volume":"102","author":"K W\u00f3jcik-Pszczo\u0142a","year":"2018","unstructured":"W\u00f3jcik-Pszczo\u0142a, K. et al. Connective tissue growth factor regulates transition of primary bronchial fibroblasts to myofibroblasts in asthmatic subjects. Cytokine 102, 187\u2013190 (2018).","journal-title":"Cytokine"},{"key":"73473_CR18","doi-asserted-by":"crossref","first-page":"326","DOI":"10.20452\/pamw.1343","volume":"122","author":"KA W\u00f3jcik","year":"2012","unstructured":"W\u00f3jcik, K. A., Koczurkiewicz, P., Michalik, M. & Sanak, M. Transforming growth factor-\u03b21-induced expression of connective tissue growth factor is enhanced in bronchial fibroblasts derived from asthmatic patients. Pol. Arch. Med. Wewn. 122, 326\u2013332 (2012).","journal-title":"Pol. Arch. Med. Wewn."},{"key":"73473_CR19","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1056\/NEJMoa0906312","volume":"363","author":"MF Moffatt","year":"2010","unstructured":"Moffatt, M. F. et al. Europe PMC Funders Group Europe PMC funders author manuscripts a large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211\u20131221 (2010).","journal-title":"N. Engl. J. Med."},{"key":"73473_CR20","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1016\/j.humimm.2016.09.011","volume":"77","author":"Y Yao","year":"2016","unstructured":"Yao, Y., Chang, W., He, L., Jin, Y. & Li, C. An updated meta-analysis of transforming growth factor-\u03b21 gene: three well-characterized polymorphisms with asthma. Hum. Immunol. 77, 1291\u20131299 (2016).","journal-title":"Hum. Immunol."},{"key":"73473_CR21","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/S1094-5539(03)00051-8","volume":"16","author":"C Duvernelle","year":"2003","unstructured":"Duvernelle, C., Freund, V. & Frossard, N. Transforming growth factor-\u03b2 and its role in asthma. Pulm. Pharmacol. Ther. 16, 181\u2013196 (2003).","journal-title":"Pulm. Pharmacol. Ther."},{"key":"73473_CR22","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1165\/rcmb.2010-0027TR","volume":"44","author":"R Halwani","year":"2011","unstructured":"Halwani, R., Al-Muhsen, S., Al-Jahdali, H. & Hamid, Q. Role of transforming growth factor-\u03b2 in airway remodeling in asthma. Am. J. Respir. Cell Mol. Biol. 44, 127\u2013133 (2011).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"73473_CR23","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1164\/ajrccm.156.2.9605065","volume":"156","author":"AE Redington","year":"1997","unstructured":"Redington, A. E. et al. Transforming growth factor-\u03b21 in asthma: measurement in bronchoalveolar lavage fluid. Am. J. Respir. Crit. Care Med. 156, 642\u2013647 (1997).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"73473_CR24","doi-asserted-by":"publisher","first-page":"45","DOI":"10.2174\/187153006776056585","volume":"6","author":"H Graham","year":"2006","unstructured":"Graham, H. & Peng, C. Activin receptor-like kinases: structure, function and clinical implications. Endocr. Metab. Immune Disord. Drug Targets 6, 45\u201358 (2006).","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"73473_CR25","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1242\/jcs.02554","volume":"118","author":"A Moustakas","year":"2005","unstructured":"Moustakas, A. & Heldin, C.-H. Non-Smad TGF-\u03b2 signals. J. Cell Sci. 118, 3573\u20133584 (2005).","journal-title":"J. Cell Sci."},{"key":"73473_CR26","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1016\/j.tcb.2017.04.005","volume":"27","author":"EH Budi","year":"2017","unstructured":"Budi, E. H., Duan, D. & Derynck, R. Transforming growth factor-\u03b2 receptors and smads: regulatory complexity and functional versatility. Trends Cell Biol. 27, 658\u2013672 (2017).","journal-title":"Trends Cell Biol."},{"key":"73473_CR27","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/nature02006","volume":"425","author":"R Derynck","year":"2003","unstructured":"Derynck, R. & Zhang, Y. E. Smad-dependent and Smad-independent pathways in TGF-\u03b2 family signalling. Nature 425, 577\u2013584 (2003).","journal-title":"Nature"},{"key":"73473_CR28","doi-asserted-by":"publisher","first-page":"2783","DOI":"10.1101\/gad.1350705","volume":"19","author":"J Massagu\u00e9","year":"2005","unstructured":"Massagu\u00e9, J., Seoane, J. & Wotton, D. Smad transcription factors. Genes Dev. 19, 2783\u20132810 (2005).","journal-title":"Genes Dev."},{"key":"73473_CR29","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1073\/pnas.98.3.974","volume":"98","author":"Y Zhang","year":"2001","unstructured":"Zhang, Y., Chang, C., Gehling, D. J., Hemmati-Brivanlou, A. & Derynck, R. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc. Natl. Acad. Sci. USA 98, 974\u2013979 (2001).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"73473_CR30","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1016\/j.bbadis.2009.06.004","volume":"1792","author":"D Pohlers","year":"2009","unstructured":"Pohlers, D. et al. TGF-\u03b2 and fibrosis in different organs\u2014molecular pathway imprints. Biochim. Biophys. Acta 1792, 746\u2013756 (2009).","journal-title":"Biochim. Biophys. Acta"},{"key":"73473_CR31","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1369\/0022155415627681","volume":"64","author":"F Xu","year":"2016","unstructured":"Xu, F., Liu, C., Zhou, D. & Zhang, L. TGF-\u03b2\/SMAD pathway and its regulation in hepatic fibrosis. J. Histochem. Cytochem. 64, 157\u2013167 (2016).","journal-title":"J. Histochem. Cytochem."},{"key":"73473_CR32","doi-asserted-by":"publisher","first-page":"196","DOI":"10.3109\/08977194.2011.595714","volume":"29","author":"A Biernacka","year":"2011","unstructured":"Biernacka, A., Dobaczewski, M. & Frangogiannis, N. G. TGF-\u03b2 signaling in fibrosis. Growth Factors 29, 196\u2013202 (2011).","journal-title":"Growth Factors"},{"key":"73473_CR33","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1111\/j.1440-1797.2005.00334.x","volume":"10","author":"W Wang","year":"2005","unstructured":"Wang, W., Koka, V. & Lan, H. Y. Transforming growth factor-\u03b2 and Smad signalling in kidney diseases. Nephrology 10, 48\u201356 (2005).","journal-title":"Nephrology"},{"key":"73473_CR34","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.pharmthera.2015.10.003","volume":"156","author":"JM Mu\u00f1oz-F\u00e9lix","year":"2015","unstructured":"Mu\u00f1oz-F\u00e9lix, J. M., Gonz\u00e1lez-N\u00fa\u00f1ez, M., Mart\u00ednez-Salgado, C. & L\u00f3pez-Novoa, J. M. TGF-\u03b2\/BMP proteins as therapeutic targets in renal fibrosis. Where have we arrived after 25 years of trials and tribulations?. Pharmacol. Ther. 156, 44\u201358 (2015).","journal-title":"Pharmacol. Ther."},{"key":"73473_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphar.2017.00318","volume":"8","author":"BL McVicker","year":"2017","unstructured":"McVicker, B. L. & Bennett, R. G. Novel anti-fibrotic therapies. Front. Pharmacol. 8, 1\u201321 (2017).","journal-title":"Front. Pharmacol."},{"key":"73473_CR36","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/206109","author":"M Michalik","year":"2012","unstructured":"Michalik, M. et al. Lithium attenuates TGF-\u03b21-induced fibroblasts to myofibroblasts transition in bronchial fibroblasts derived from asthmatic patients. J. Allergy https:\/\/doi.org\/10.1155\/2012\/206109 (2012).","journal-title":"J. Allergy"},{"key":"73473_CR37","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ejphar.2013.02.023","volume":"704","author":"M Michalik","year":"2013","unstructured":"Michalik, M. et al. Lovastatin-induced decrease of intracellular cholesterol level attenuates fibroblast-to-myofibroblast transition in bronchial fibroblasts derived from asthmatic patients. Eur. J. Pharmacol. 704, 23\u201332 (2013).","journal-title":"Eur. J. Pharmacol."},{"key":"73473_CR38","doi-asserted-by":"publisher","first-page":"2571","DOI":"10.3390\/ijms19092571","volume":"19","author":"M Paw","year":"2018","unstructured":"Paw, M. et al. Fenofibrate reduces the asthma-related fibroblast-to-myofibroblast transition by TGF-\u0392\/Smad2\/3 signaling attenuation and connexin 43-dependent phenotype destabilization. Int. J. Mol. Sci. 19, 2571 (2018).","journal-title":"Int. J. Mol. Sci."},{"key":"73473_CR39","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1016\/j.cytogfr.2013.08.002","volume":"24","author":"JM Mu\u00f1oz-F\u00e9lix","year":"2013","unstructured":"Mu\u00f1oz-F\u00e9lix, J. M., Gonz\u00e1lez-N\u00fa\u00f1ez, M. & L\u00f3pez-Novoa, J. M. ALK1-Smad1\/5 signaling pathway in fibrosis development: Friend or foe?. Cytokine Growth Factor Rev. 24, 523\u2013537 (2013).","journal-title":"Cytokine Growth Factor Rev."},{"key":"73473_CR40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep36655","volume":"6","author":"V Dexheimer","year":"2016","unstructured":"Dexheimer, V. et al. Differential expression of TGF-\u03b2 superfamily members and role of Smad1\/5\/9-signalling in chondral versus endochondral chondrocyte differentiation. Sci. Rep. 6, 1\u201314 (2016).","journal-title":"Sci. Rep."},{"key":"73473_CR41","first-page":"307","volume":"56","author":"H Jaiswal","year":"2017","unstructured":"Jaiswal, H., Dev, D. S. & Kisku, D. R. Rank order reduction based fast pattern matching algorithm. Gut 56, 307\u2013322 (2017).","journal-title":"Gut"},{"key":"73473_CR42","doi-asserted-by":"publisher","first-page":"4992","DOI":"10.2741\/3583","volume":"14","author":"R Weiskirchen","year":"2009","unstructured":"Weiskirchen, R. BMP-7 as antagonist of organ fibrosis. Front. Biosci. 14, 4992 (2009).","journal-title":"Front. Biosci."},{"key":"73473_CR43","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1046\/j.1365-2443.2002.00599.x","volume":"7","author":"K Miyazawa","year":"2002","unstructured":"Miyazawa, K., Shinozaki, M., Hara, T., Furuya, T. & Miyazono, K. Two major Smad pathways in TGF-\u03b2 superfamily signalling. Genes Cells 7, 1191\u20131204 (2002).","journal-title":"Genes Cells"},{"key":"73473_CR44","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.gendis.2014.07.005","volume":"1","author":"RN Wang","year":"2014","unstructured":"Wang, R. N. et al. Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis. 1, 87\u2013105 (2014).","journal-title":"Genes Dis."},{"key":"73473_CR45","doi-asserted-by":"publisher","first-page":"e59045","DOI":"10.1371\/journal.pone.0059045","volume":"8","author":"K Vrijens","year":"2013","unstructured":"Vrijens, K. et al. Identification of small molecule activators of BMP signaling. PLoS ONE 8, e59045 (2013).","journal-title":"PLoS ONE"},{"key":"73473_CR46","doi-asserted-by":"publisher","first-page":"e13669","DOI":"10.14814\/phy2.13669","volume":"6","author":"J Breton","year":"2018","unstructured":"Breton, J., Heydet, D., Starrs, L. M., Veldre, T. & Ghildyal, R. Molecular changes during TGF \u03b2-mediated lung fibroblast-myofibroblast differentiation: implication for glucocorticoid resistance. Physiol. Rep. 6, e13669 (2018).","journal-title":"Physiol. Rep."},{"key":"73473_CR47","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.redox.2016.06.005","volume":"9","author":"A Kurundkar","year":"2016","unstructured":"Kurundkar, A. & Thannickal, V. J. Redox mechanisms in age-related lung fibrosis. Redox Biol. 9, 67\u201376 (2016).","journal-title":"Redox Biol."},{"key":"73473_CR48","doi-asserted-by":"publisher","first-page":"458276","DOI":"10.1155\/2012\/458276","volume":"2012","author":"N Sampson","year":"2012","unstructured":"Sampson, N., Berger, P. & Zenzmaier, C. Therapeutic targeting of redox signaling in myofibroblast differentiation and age-related fibrotic disease. Oxid. Med. Cell. Longev. 2012, 458276 (2012).","journal-title":"Oxid. Med. Cell. Longev."},{"key":"73473_CR49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphar.2017.00461","volume":"8","author":"KL Walton","year":"2017","unstructured":"Walton, K. L., Johnson, K. E. & Harrison, C. A. Targeting TGF-\u03b2 Mediated SMAD signaling for the prevention of fibrosis. Front. Pharmacol. 8, 1\u201311 (2017).","journal-title":"Front. Pharmacol."},{"key":"73473_CR50","doi-asserted-by":"publisher","first-page":"109","DOI":"10.5603\/ARM.2017.0017","volume":"85","author":"M Ko\u0107win","year":"2017","unstructured":"Ko\u0107win, M., Jonakowski, M., Przem\u0119cka, M., Panek, M. & Kuna, P. Selected bone morphogenetic proteins\u2014the possibility of their use in the diagnostics and therapy of severe asthma. Adv. Respir. Med. 85, 109\u2013115 (2017).","journal-title":"Adv. Respir. Med."},{"key":"73473_CR51","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1067\/mai.2002.126078","volume":"110","author":"H Sagara","year":"2002","unstructured":"Sagara, H. et al. Activation of TGF-\u03b2\/Smad2 signaling is associated with airway remodeling in asthma. J. Allergy Clin. Immunol. 110, 249\u2013254 (2002).","journal-title":"J. Allergy Clin. Immunol."},{"key":"73473_CR52","doi-asserted-by":"publisher","first-page":"25","DOI":"10.4168\/aair.2017.9.1.25","volume":"9","author":"HY Lee","year":"2017","unstructured":"Lee, H. Y. et al. Inhibitory effects of resveratrol on airway remodeling by transforming growth factor-\u03b2\/smad signaling pathway in chronic asthma model. Allergy Asthma Immunol. Res. 9, 25\u201334 (2017).","journal-title":"Allergy Asthma Immunol. Res."},{"key":"73473_CR53","doi-asserted-by":"publisher","first-page":"564","DOI":"10.3892\/ijmm.2011.868","volume":"29","author":"ZH Qu","year":"2012","unstructured":"Qu, Z. H. et al. Inhibition airway remodeling and transforming growth factor-\u03b21\/Smad signaling pathway by astragalus extract in asthmatic mice. Int. J. Mol. Med. 29, 564\u2013568 (2012).","journal-title":"Int. J. Mol. Med."},{"key":"73473_CR54","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1136\/thx.2006.063487","volume":"62","author":"A Torrego","year":"2007","unstructured":"Torrego, A., Hew, M., Oates, T., Sukkar, M. & Kian, F. C. Expression and activation of TGF-\u03b2 isoforms in acute allergen-induced remodelling in asthma. Thorax 62, 307\u2013313 (2007).","journal-title":"Thorax"},{"key":"73473_CR55","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1016\/j.jaci.2009.06.022","volume":"124","author":"HH Kariyawasam","year":"2009","unstructured":"Kariyawasam, H. H. et al. Activin and transforming growth factor-\u03b2 signaling pathways are activated after allergen challenge in mild asthma. J. Allergy Clin. Immunol. 124, 454\u2013462 (2009).","journal-title":"J. Allergy Clin. Immunol."},{"key":"73473_CR56","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.plefa.2011.11.001","volume":"86","author":"R Eap","year":"2012","unstructured":"Eap, R., Jacques, E., Semlali, A., Plante, S. & Chakir, J. Cysteinyl leukotrienes regulate TGF-\u03921 and collagen production by bronchial fibroblasts obtained from asthmatic subjects. Prostaglandins Leukot. Essent. Fat. Acids 86, 127\u2013133 (2012).","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"73473_CR57","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1055\/s-0042-117537","volume":"82","author":"P Koczurkiewicz","year":"2016","unstructured":"Koczurkiewicz, P. et al. Synergistic cytotoxic and anti-invasive effects of mitoxantrone and triterpene saponins from lysimachia ciliata on human prostate cancer cells. Planta Med. 82, 1546\u20131552 (2016).","journal-title":"Planta Med."},{"key":"73473_CR58","doi-asserted-by":"publisher","first-page":"9755","DOI":"10.1074\/jbc.M809223200","volume":"284","author":"KH Wrighton","year":"2009","unstructured":"Wrighton, K. H., Lin, X., Yu, P. B. & Feng, X. H. Transforming growth factor \u03b2 can stimulate Smad1 phosphorylation independently of bone morphogenic protein receptors. J. Biol. Chem. 284, 9755\u20139763 (2009).","journal-title":"J. Biol. Chem."},{"key":"73473_CR59","doi-asserted-by":"publisher","first-page":"L615","DOI":"10.1152\/ajpcell.00249.2016","volume":"313","author":"H Zhang","year":"2017","unstructured":"Zhang, H., Du, L., Zhong, Y., Flanders, K. C. & Roberts, J. D. Transforming growth factor-\u03b2 stimulates Smad1\/5 signaling in pulmonary artery smooth muscle cells and fibroblasts of the newborn mouse through ALK1. Am. J. Physiol. 313, L615\u2013L627 (2017).","journal-title":"Am. J. Physiol."},{"key":"73473_CR60","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1042\/CS20120252","volume":"124","author":"X-M Meng","year":"2013","unstructured":"Meng, X.-M., Chung, A. C. K. & Lan, H. Y. Role of the TGF-\u03b2\/BMP-7\/Smad pathways in renal diseases. Clin. Sci. 124, 243\u2013254 (2013).","journal-title":"Clin. Sci."},{"key":"73473_CR61","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1371\/journal.pone.0095959","volume":"9","author":"CL Stumm","year":"2014","unstructured":"Stumm, C. L. et al. Lung remodeling in a mouse model of asthma involves a balance between TGF-\u03b21 and BMP-7. PLoS ONE 9, 3\u201311 (2014).","journal-title":"PLoS ONE"},{"key":"73473_CR62","doi-asserted-by":"publisher","first-page":"L120","DOI":"10.1152\/ajplung.00171.2005","volume":"290","author":"N Izumi","year":"2006","unstructured":"Izumi, N. et al. BMP-7 opposes TGF-\u03b21-mediated collagen induction in mouse pulmonary myofibroblasts through Id2. Am. J. Physiol. Cell. Mol. Physiol. 290, L120\u2013L126 (2006).","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"73473_CR63","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.cbi.2015.11.012","volume":"243","author":"D Liang","year":"2016","unstructured":"Liang, D. et al. BMP-7 attenuated silica-induced pulmonary fibrosis through modulation of the balance between TGF-\u03b2\/Smad and BMP-7\/Smad signaling pathway. Chem. Biol. Interact. 243, 72\u201381 (2016).","journal-title":"Chem. Biol. Interact."},{"key":"73473_CR64","doi-asserted-by":"publisher","first-page":"3457","DOI":"10.12659\/MSM.897560","volume":"22","author":"X Chen","year":"2016","unstructured":"Chen, X., Xu, J., Jiang, B. & Liu, D. Bone morphogenetic protein-7 antagonizes myocardial fibrosis induced by atrial fibrillation by restraining transforming growth factor-\u03b2 (TGF-\u03b2)\/Smads signaling. Med. Sci. Monit. 22, 3457\u20133468 (2016).","journal-title":"Med. Sci. Monit."},{"key":"73473_CR65","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1164\/rccm.200709-1376OC","volume":"177","author":"HH Kariyawasam","year":"2008","unstructured":"Kariyawasam, H. H. et al. Basal expression of bone morphogenetic protein receptor is reduced in mild asthma. Am. J. Respir. Crit. Care Med. 177, 1074\u20131081 (2008).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"73473_CR66","doi-asserted-by":"publisher","first-page":"4777","DOI":"10.1038\/emboj.2011.393","volume":"30","author":"LY Tang","year":"2011","unstructured":"Tang, L. Y. et al. Ablation of Smurf2 reveals an inhibition in TGF-\u03b2 signalling through multiple mono-ubiquitination of Smad3. EMBO J. 30, 4777\u20134789 (2011).","journal-title":"EMBO J."},{"key":"73473_CR67","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/1465-9921-11-85","volume":"11","author":"S Pegorier","year":"2010","unstructured":"Pegorier, S., Campbell, G. A., Kay, A. B. & Lloyd, C. M. Bone morphogenetic protein (BMP)-4 and BMP-7 regulate differentially transforming growth factor (TGF)-\u03b21 in normal human lung fibroblasts (NHLF). Respir. Res. 11, 85 (2010).","journal-title":"Respir. Res."},{"key":"73473_CR68","doi-asserted-by":"publisher","first-page":"11218","DOI":"10.1074\/jbc.M114.625939","volume":"290","author":"AC Midgley","year":"2015","unstructured":"Midgley, A. C. et al. Hyaluronan regulates bone morphogenetic protein-7-dependent prevention and reversal of myofibroblast phenotype. J. Biol. Chem. 290, 11218\u201311234 (2015).","journal-title":"J. Biol. Chem."},{"key":"73473_CR69","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1002\/ptr.4862","volume":"27","author":"N Yang","year":"2013","unstructured":"Yang, N. et al. Glycyrrhiza uralensis flavonoids present in anti-asthma formula, ASHMITM, inhibit memory Th2 responses in vitro and in vivo. Phyther. Res. 27, 1381\u20131391 (2013).","journal-title":"Phyther. Res."},{"key":"73473_CR70","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.jaci.2005.05.029","volume":"116","author":"MC Wen","year":"2005","unstructured":"Wen, M. C. et al. Efficacy and tolerability of antiasthma herbal medicine intervention in adult patients with moderate-severe allergic asthma. J. Allergy Clin. Immunol. 116, 517\u2013524 (2005).","journal-title":"J. Allergy Clin. Immunol."},{"key":"73473_CR71","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.ejphar.2008.03.015","volume":"587","author":"B Liu","year":"2008","unstructured":"Liu, B., Yang, J., Wen, Q. & Li, Y. Isoliquiritigenin, a flavonoid from licorice, relaxes guinea-pig tracheal smooth muscle in vitro and in vivo: Role of cGMP\/PKG pathway. Eur. J. Pharmacol. 587, 257\u2013266 (2008).","journal-title":"Eur. J. Pharmacol."},{"key":"73473_CR72","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/s41598-016-0011-6","volume":"6","author":"Y Watanabe","year":"2016","unstructured":"Watanabe, Y. et al. Isoliquiritigenin attenuates adipose tissue inflammation in vitro and adipose tissue fibrosis through inhibition of innate immune responses in mice. Sci. Rep. 6, 4\u20136 (2016).","journal-title":"Sci. Rep."},{"key":"73473_CR73","first-page":"1","volume":"2019","author":"H Jin","year":"2019","unstructured":"Jin, H. et al. Isoliquiritigenin attenuates monocrotaline-induced pulmonary hypertension via inhibition of the inflammatory response and PASMCs proliferation. Evid.-Based Complement. Altern. Med. 2019, 1\u201310 (2019).","journal-title":"Evid.-Based Complement. Altern. Med."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-73473-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-73473-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-73473-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T09:34:59Z","timestamp":1723714499000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-73473-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,5]]},"references-count":73,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["73473"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-73473-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,5]]},"assertion":[{"value":"17 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 July 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 October 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16492"}}