دورية أكاديمية
β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis.
| العنوان: | β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis. |
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| المؤلفون: | Vijftigschild LA; Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands These two authors contributed equally to this work., Berkers G; Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands These two authors contributed equally to this work., Dekkers JF; Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands These two authors contributed equally to this work., Zomer-van Ommen DD; Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands These two authors contributed equally to this work., Matthes E; CF Translational Research Centre, Dept of Physiology, McGill University, Montréal, QC, Canada., Kruisselbrink E; Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands., Vonk A; Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands., Hensen CE; Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands., Heida-Michel S; Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands., Geerdink M; Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands., Janssens HM; Dept of Pediatric Pulmonology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands., van de Graaf EA; Dept of Pulmonology, University Medical Center, Utrecht, The Netherlands., Bronsveld I; Dept of Pulmonology, University Medical Center, Utrecht, The Netherlands., de Winter-de Groot KM; Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands., Majoor CJ; Dept of Respiratory Medicine, Academic Medical Center, Amsterdam, The Netherlands., Heijerman HG; Dept of Pulmonology and Cystic Fibrosis, Haga Teaching Hospital, The Hague, The Netherlands., de Jonge HR; Dept of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands., Hanrahan JW; CF Translational Research Centre, Dept of Physiology, McGill University, Montréal, QC, Canada., van der Ent CK; Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands., Beekman JM; Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands Regenerative Medicine Center Utrecht, University Medical Center, Utrecht, The Netherlands jbeekman@umcutrecht.nl. |
| المصدر: | The European respiratory journal [Eur Respir J] 2016 Sep; Vol. 48 (3), pp. 768-79. Date of Electronic Publication: 2016 Jul 28. |
| نوع المنشور: | Clinical Trial, Phase II; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: European Respiratory Society Country of Publication: England NLM ID: 8803460 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1399-3003 (Electronic) Linking ISSN: 09031936 NLM ISO Abbreviation: Eur Respir J Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Sheffield, United Kingdom : European Respiratory Society Original Publication: Copenhagen : Published jointly by the Society and Munksgaard, 1988- |
| مواضيع طبية MeSH: | Adrenergic beta-2 Receptor Agonists/*pharmacology , Cystic Fibrosis/*drug therapy , Cystic Fibrosis/*metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/*metabolism, Administration, Oral ; Albuterol/administration & dosage ; Biological Assay ; Bronchi/pathology ; Cell Line ; Cells, Cultured ; Chlorides/chemistry ; Cystic Fibrosis/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Drug Evaluation, Preclinical ; Epithelial Cells/metabolism ; Epithelium/metabolism ; Humans ; Mutation ; Nasal Mucosa/drug effects ; Nasal Mucosa/metabolism ; Organoids ; Pilot Projects ; Respiratory System/metabolism ; Signal Transduction |
| مستخلص: | We hypothesized that people with cystic fibrosis (CF) who express CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations associated with residual function may benefit from G-protein coupled receptor (GPCR)-targeting drugs that can activate and enhance CFTR function.We used intestinal organoids to screen a GPCR-modulating compound library and identified β2-adrenergic receptor agonists as the most potent inducers of CFTR function.β2-Agonist-induced organoid swelling correlated with the CFTR genotype, and could be induced in homozygous CFTR-F508del organoids and highly differentiated primary CF airway epithelial cells after rescue of CFTR trafficking by small molecules. The in vivo response to treatment with an oral or inhaled β2-agonist (salbutamol) in CF patients with residual CFTR function was evaluated in a pilot study. 10 subjects with a R117H or A455E mutation were included and showed changes in the nasal potential difference measurement after treatment with oral salbutamol, including a significant improvement of the baseline potential difference of the nasal mucosa (+6.35 mV, p<0.05), suggesting that this treatment might be effective in vivo Furthermore, plasma that was collected after oral salbutamol treatment induced CFTR activation when administered ex vivo to organoids.This proof-of-concept study suggests that organoids can be used to identify drugs that activate CFTR function in vivo and to select route of administration. (Copyright ©ERS 2016.) |
| معلومات مُعتمدة: | Canada CIHR |
| المشرفين على المادة: | 0 (Adrenergic beta-2 Receptor Agonists) 0 (CFTR protein, human) 0 (Chlorides) 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) QF8SVZ843E (Albuterol) |
| تواريخ الأحداث: | Date Created: 20160730 Date Completed: 20180405 Latest Revision: 20180508 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1183/13993003.01661-2015 |
| PMID: | 27471203 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1399-3003 |
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| DOI: | 10.1183/13993003.01661-2015 |