{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:31:58Z","timestamp":1790757118023,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004489","name":"Mitacs","doi-asserted-by":"publisher","award":["IT11095"],"award-info":[{"award-number":["IT11095"]}],"id":[{"id":"10.13039\/501100004489","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004489","name":"Mitacs","doi-asserted-by":"publisher","award":["332196"],"award-info":[{"award-number":["332196"]}],"id":[{"id":"10.13039\/501100004489","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["IT11095"],"award-info":[{"award-number":["IT11095"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["332196"],"award-info":[{"award-number":["332196"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Genome-wide association studies (GWAS) have shown that variants of patched homolog 1 (PTCH1) are associated with lung function abnormalities in the general population. It has also been shown that sonic hedgehog (SHH), an important ligand for PTCH1, is upregulated in the airway epithelium of patients with asthma and is suggested to be involved in airway remodeling. The contribution of hedgehog signaling to airway remodeling and inflammation in asthma is poorly described. To determine the biological role of hedgehog signaling-associated genes in asthma, gene silencing, over-expression, and pharmacologic inhibition studies were conducted after stimulating human airway epithelial cells or not with transforming growth factor \u03b21 (TGF\u03b21), an important fibrotic mediator in asthmatic airway remodeling that also interacts with SHH pathway. TGF\u03b21 increased hedgehog-signaling-related gene expression including SHH, GLI1 and GLI2. Knockdown of PTCH1 or SMO with siRNA, or use of hedgehog signaling inhibitors, consistently attenuated COL1A1 expression induced by TGF\u03b21 stimulation. In contrast, Ptch1 over-expression augmented TGF\u03b21-induced an increase in COL1A1 and MMP2 gene expression. We also showed an increase in hedgehog-signaling-related gene expression in primary airway epithelial cells from controls and asthmatics at different stages of cellular differentiation. GANT61, an inhibitor of GLI1\/2, attenuated TGF\u03b21-induced increase in COL1A1 protein expression in primary airway epithelial cells differentiated in air\u2013liquid interface. Finally, to model airway tissue remodeling in vivo, C57BL\/6 wildtype (WT) and Ptch1+\/\u2212 mice were intranasally challenged with house dust mite (HDM) or phosphate-buffered saline (PBS) control. Ptch1+\/\u2212 mice showed reduced sub-epithelial collagen expression and serum inflammatory proteins compared to WT mice in response to HDM challenge. In conclusion, TGF\u03b21-induced airway remodeling is partially mediated through the hedgehog signaling pathway via the PTCH1-SMO-GLI axis. The Hedgehog signaling pathway is a promising new potential therapeutic target to alleviate airway tissue remodeling in patients with allergic airways disease.<\/jats:p>","DOI":"10.3390\/cells11193016","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T21:23:27Z","timestamp":1664313807000},"page":"3016","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Hedgehog Signaling as a Therapeutic Target for Airway Remodeling and Inflammation in Allergic Asthma"],"prefix":"10.3390","volume":"11","author":[{"given":"Anthony","family":"Tam","sequence":"first","affiliation":[{"name":"Centre for Heart Lung Innovation, St. Paul\u2019s Hospital, Vancouver, BC V6Z 1Y6, Canada"},{"name":"Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 0B3, 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Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen X.","family":"Yang","sequence":"additional","affiliation":[{"name":"Centre for Heart Lung Innovation, St. Paul\u2019s Hospital, Vancouver, BC V6Z 1Y6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4737-3499","authenticated-orcid":false,"given":"Kelly M.","family":"McNagny","sequence":"additional","affiliation":[{"name":"Centre for Heart Lung Innovation, St. Paul\u2019s Hospital, Vancouver, BC V6Z 1Y6, Canada"},{"name":"School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delbert R.","family":"Dorscheid","sequence":"additional","affiliation":[{"name":"Centre for Heart Lung Innovation, St. Paul\u2019s Hospital, Vancouver, BC V6Z 1Y6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8422-0857","authenticated-orcid":false,"given":"Gurpreet K.","family":"Singhera","sequence":"additional","affiliation":[{"name":"Centre for Heart Lung Innovation, St. Paul\u2019s Hospital, Vancouver, BC V6Z 1Y6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teal S.","family":"Hallstrand","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep Medicine and the Center for Lung Biology, University of Washington, Seattle, WA 98195-6522, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Warner","sequence":"additional","affiliation":[{"name":"Centre for Heart Lung Innovation, St. Paul\u2019s Hospital, Vancouver, BC V6Z 1Y6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James C.","family":"Hogg","sequence":"additional","affiliation":[{"name":"Centre for Heart Lung 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Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1016\/j.rmed.2014.08.008","article-title":"Transforming growth factor beta and severe asthma: A perfect storm","volume":"108","author":"Hassan","year":"2014","journal-title":"Respir. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1067\/mai.2002.126078","article-title":"Activation of TGF-beta\/Smad2 signaling is associated with airway remodeling in asthma","volume":"110","author":"Sagara","year":"2002","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1165\/rcmb.2010-0027TR","article-title":"Role of transforming growth factor-beta in airway remodeling in asthma","volume":"44","author":"Halwani","year":"2011","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nri3786","article-title":"Type 2 inflammation in asthma\u2014present in most, absent in many","volume":"15","author":"Fahy","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/S2213-2600(15)00380-X","article-title":"Molecular mechanisms underlying variations in lung function: A systems genetics analysis","volume":"3","author":"Obeidat","year":"2015","journal-title":"Lancet Respir. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/j.jaci.2011.01.056","article-title":"Importance of hedgehog interacting protein and other lung function genes in asthma","volume":"127","author":"Li","year":"2011","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1038\/nrd2086","article-title":"Targeting the Hedgehog pathway in cancer","volume":"5","author":"Rubin","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12964-018-0220-7","article-title":"A highlight on Sonic hedgehog pathway","volume":"16","author":"Carballo","year":"2018","journal-title":"Cell Commun. Signal."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/B978-0-12-394622-5.00003-1","article-title":"Noncanonical Hedgehog signaling","volume":"88","author":"Brennan","year":"2012","journal-title":"Vitam. Horm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nrc3079","article-title":"The Hedgehog\u2019s tale: Developing strategies for targeting cancer","volume":"11","author":"Ng","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1126\/science.280.5369.1603","article-title":"Teratogen-mediated inhibition of target tissue response to Shh signaling","volume":"280","author":"Cooper","year":"1998","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1038\/35023008","article-title":"Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine","volume":"406","author":"Taipale","year":"2000","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1158\/1535-7163.MCT-11-0705","article-title":"Off-target function of the Sonic hedgehog inhibitor cyclopamine in mediating apoptosis via nitric oxide-dependent neutral sphingomyelinase 2\/ceramide induction","volume":"11","author":"Lewis","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8455","DOI":"10.1073\/pnas.0609699104","article-title":"Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists","volume":"104","author":"Lauth","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1038\/s41385-018-0033-4","article-title":"High expression of Sonic hedgehog in allergic airway epithelia contributes to goblet cell metaplasia","volume":"11","author":"Xu","year":"2018","journal-title":"Mucosal. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Johnson, J.R., Roos, A., Berg, T., Nord, M., and Fuxe, J. (2011). Chronic respiratory aeroallergen exposure in mice induces epithelial-mesenchymal transition in the large airways. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016175"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1111\/j.1365-2222.2009.03302.x","article-title":"Inhaled house dust mite induces pulmonary T helper 2 cytokine production","volume":"39","author":"Gregory","year":"2009","journal-title":"Clin. Exp. Allergy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1189\/jlb.3HI1016-438RR","article-title":"Frontline Science: Shh production and Gli signaling is activated in vivo in lung, enhancing the Th2 response during a murine model of allergic asthma","volume":"102","author":"Standing","year":"2017","journal-title":"J. Leukoc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"L888","DOI":"10.1152\/ajplung.00186.2019","article-title":"IL-4\/IL-13 upregulates Sonic hedgehog expression to induce allergic airway epithelial remodeling","volume":"318","author":"Wang","year":"2020","journal-title":"Am. J. Physiol. Lung. Cell. Mol. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1164\/rccm.200811-1730OC","article-title":"Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1","volume":"180","author":"Hackett","year":"2009","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/cr.2008.302","article-title":"Signaling cross-talk between TGF-beta\/BMP and other pathways","volume":"19","author":"Guo","year":"2009","journal-title":"Cell Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1016\/j.febslet.2012.05.011","article-title":"Crosstalk between TGF-beta and hedgehog signaling in cancer","volume":"586","author":"Javelaud","year":"2012","journal-title":"FEBS Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5951","DOI":"10.1073\/pnas.85.16.5951","article-title":"Characterization of human tracheal epithelial cells transformed by an origin-defective simian virus 40","volume":"85","author":"Gruenert","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1126\/science.1139740","article-title":"Patched1 regulates hedgehog signaling at the primary cilium","volume":"317","author":"Rohatgi","year":"2007","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Tam, A., Wadsworth, S., Dorscheid, D., Man, S.F., and Sin, D.D. (2014). Estradiol increases mucus synthesis in bronchial epithelial cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100633"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1038\/s41598-019-40045-3","article-title":"Hedgehog signaling in the airway epithelium of patients with chronic obstructive pulmonary disease","volume":"9","author":"Tam","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8721","DOI":"10.1038\/s41598-020-65567-z","article-title":"Epithelial-interleukin-1 inhibits collagen formation by airway fibroblasts: Implications for asthma","volume":"10","author":"Osei","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1165\/rcmb.2011-0031OC","article-title":"Intrinsic phenotypic differences of asthmatic epithelium and its inflammatory responses to respiratory syncytial virus and air pollution","volume":"45","author":"Hackett","year":"2011","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Li, B., and Dewey, C.N. (2011). RSEM: Accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-323"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1126\/science.277.5329.1109","article-title":"Altered neural cell fates and medulloblastoma in mouse patched mutants","volume":"277","author":"Goodrich","year":"1997","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1016\/j.jaci.2014.02.033","article-title":"Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures","volume":"133","author":"Gold","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1378\/chest.124.1.32","article-title":"Histopathology of severe childhood asthma: A case series","volume":"124","author":"Jenkins","year":"2003","journal-title":"Chest"},{"key":"ref_34","first-page":"2173","article-title":"Gene expression profiling of epithelial-mesenchymal transition in primary breast cancer cell culture","volume":"34","author":"Minafra","year":"2014","journal-title":"Anticancer. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"L414","DOI":"10.1152\/ajplung.00346.2010","article-title":"Epithelial EGF receptor signaling mediates airway hyperreactivity and remodeling in a mouse model of chronic asthma","volume":"300","author":"Acciani","year":"2011","journal-title":"Am. J. Physiol. Lung. Cell Mol. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"46166","DOI":"10.1038\/srep46166","article-title":"Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice","volume":"7","author":"Sharma","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_37","first-page":"4674","article-title":"House dust mite induces Sonic hedgehog signaling that mediates epithelialmesenchymal transition in human bronchial epithelial cells","volume":"20","author":"Zou","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1016\/j.ajpath.2012.08.019","article-title":"The hedgehog system machinery controls transforming growth factor-beta-dependent myofibroblastic differentiation in humans: Involvement in idiopathic pulmonary fibrosis","volume":"181","author":"Cigna","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1165\/rcmb.2014-0108OC","article-title":"Reemergence of hedgehog mediates epithelial-mesenchymal crosstalk in pulmonary fibrosis","volume":"52","author":"Hu","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41374-019-0316-8","article-title":"The Shh\/Gli signaling cascade regulates myofibroblastic activation of lung-resident mesenchymal stem cells via the modulation of Wnt10a expression during pulmonary fibrogenesis","volume":"100","author":"Cao","year":"2020","journal-title":"Lab. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/dvdy.20105","article-title":"Role of Sonic hedgehog in patterning of tracheal-bronchial cartilage and the peripheral lung","volume":"231","author":"Miller","year":"2004","journal-title":"Dev. Dyn."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1165\/rcmb.2013-0154OC","article-title":"Targeting the hedgehog-glioma-associated oncogene homolog pathway inhibits bleomycin-induced lung fibrosis in mice","volume":"51","author":"Moshai","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.tips.2015.09.001","article-title":"Smoothened Regulation: A Tale of Two Signals","volume":"37","author":"Arensdorf","year":"2016","journal-title":"Trends Pharmacol. Sci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/19\/3016\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:40:21Z","timestamp":1760143221000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/19\/3016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,27]]},"references-count":43,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["cells11193016"],"URL":"https:\/\/doi.org\/10.3390\/cells11193016","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,27]]}}}