Stimulation of airway and intestinal mucosal secretion by natural coumarin CFTR activators
Mutations of cystic fibrosis transmembrane conductance regulator (CFTR) cause lethal hereditary disease cystic fibrosis (CF) that involves extensive destruction and dysfunction of serous epithelium. Possible pharmacological therapy includes correction of defective intracellular processing and abnorm...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2011-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphar.2011.00052/full |
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| author | Hong eYang Lina eXu Yujie eSui Xin eLiu Chengyan eHe Rouyu eFang Jia eLiu Feng eHao Tong-Hui eMa Tong-Hui eMa |
| author_facet | Hong eYang Lina eXu Yujie eSui Xin eLiu Chengyan eHe Rouyu eFang Jia eLiu Feng eHao Tong-Hui eMa Tong-Hui eMa |
| author_sort | Hong eYang |
| collection | DOAJ |
| description | Mutations of cystic fibrosis transmembrane conductance regulator (CFTR) cause lethal hereditary disease cystic fibrosis (CF) that involves extensive destruction and dysfunction of serous epithelium. Possible pharmacological therapy includes correction of defective intracellular processing and abnormal channel gating. In a previous study, we identified five natural coumarin potentiators of Δ508-CFTR including osthole, imperatorin, isopsoralen, praeruptorin A and scoparone. The present study was designed to determine the activity of these coumarine compounds on CFTR activity in animal tissues as a primary evaluation of their therapeutic potential. In the present study, we analyzed the affinity of these coumarin potentiators in activating wild-type CFTR and found that they are all potent activators. Osthole showed the highest affinity with Kd values <50 nmol/L as determined by Ussing chamber short-circuit current assay. Stimulation of rat colonic mucosal secretion by osthole was tested by the Ussing chamber short-circuit current assay. Osthole reached maximal activation of colonic Cl- secretion at 5 mol/L. Stimulation of mouse tracheal mucosal secretion was analyzed by optical measurement of single gland secretion. Fluid secretion rate of tracheal single submucosal gland stimulated by osthole at 10mol/L was 3-fold more rapid than that in negative control. In both cases the stimulated secretions were fully abolished by CFTRinh-172. In conclusion, the effective stimulation of Cl– and fluid secretion in colonic and tracheal mucosa by osthole suggested the therapeutic potential of natural coumarine compounds for the treatment of cystic fibrosis and other CFTR-related diseases. |
| first_indexed | 2024-04-12T10:21:54Z |
| format | Article |
| id | doaj.art-c65d62ea1ff14a83a16d64b10d8b31e8 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T10:21:54Z |
| publishDate | 2011-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-c65d62ea1ff14a83a16d64b10d8b31e82022-12-22T03:37:04ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122011-09-01210.3389/fphar.2011.0005210304Stimulation of airway and intestinal mucosal secretion by natural coumarin CFTR activatorsHong eYang0Lina eXu1Yujie eSui2Xin eLiu3Chengyan eHe4Rouyu eFang5Jia eLiu6Feng eHao7Tong-Hui eMa8Tong-Hui eMa9Liaoning Normal UniversityJilin University Bethune Second HospitalJilin University Bethune Second HospitalJilin UniversityJilin UniversityJilin University Bethune Second HospitalJilin University Bethune Second HospitalJilin University Bethune Second HospitalLiaoning Normal UniversityJilin University Bethune Second HospitalMutations of cystic fibrosis transmembrane conductance regulator (CFTR) cause lethal hereditary disease cystic fibrosis (CF) that involves extensive destruction and dysfunction of serous epithelium. Possible pharmacological therapy includes correction of defective intracellular processing and abnormal channel gating. In a previous study, we identified five natural coumarin potentiators of Δ508-CFTR including osthole, imperatorin, isopsoralen, praeruptorin A and scoparone. The present study was designed to determine the activity of these coumarine compounds on CFTR activity in animal tissues as a primary evaluation of their therapeutic potential. In the present study, we analyzed the affinity of these coumarin potentiators in activating wild-type CFTR and found that they are all potent activators. Osthole showed the highest affinity with Kd values <50 nmol/L as determined by Ussing chamber short-circuit current assay. Stimulation of rat colonic mucosal secretion by osthole was tested by the Ussing chamber short-circuit current assay. Osthole reached maximal activation of colonic Cl- secretion at 5 mol/L. Stimulation of mouse tracheal mucosal secretion was analyzed by optical measurement of single gland secretion. Fluid secretion rate of tracheal single submucosal gland stimulated by osthole at 10mol/L was 3-fold more rapid than that in negative control. In both cases the stimulated secretions were fully abolished by CFTRinh-172. In conclusion, the effective stimulation of Cl– and fluid secretion in colonic and tracheal mucosa by osthole suggested the therapeutic potential of natural coumarine compounds for the treatment of cystic fibrosis and other CFTR-related diseases.http://journal.frontiersin.org/Journal/10.3389/fphar.2011.00052/fullColonCoumarinsairwayCFTRMucosaactivator |
| spellingShingle | Hong eYang Lina eXu Yujie eSui Xin eLiu Chengyan eHe Rouyu eFang Jia eLiu Feng eHao Tong-Hui eMa Tong-Hui eMa Stimulation of airway and intestinal mucosal secretion by natural coumarin CFTR activators Frontiers in Pharmacology Colon Coumarins airway CFTR Mucosa activator |
| title | Stimulation of airway and intestinal mucosal secretion by natural coumarin CFTR activators |
| title_full | Stimulation of airway and intestinal mucosal secretion by natural coumarin CFTR activators |
| title_fullStr | Stimulation of airway and intestinal mucosal secretion by natural coumarin CFTR activators |
| title_full_unstemmed | Stimulation of airway and intestinal mucosal secretion by natural coumarin CFTR activators |
| title_short | Stimulation of airway and intestinal mucosal secretion by natural coumarin CFTR activators |
| title_sort | stimulation of airway and intestinal mucosal secretion by natural coumarin cftr activators |
| topic | Colon Coumarins airway CFTR Mucosa activator |
| url | http://journal.frontiersin.org/Journal/10.3389/fphar.2011.00052/full |
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