Activation of Intestinal Cl− Secretion by Lubiprostone Requires the Cystic Fibrosis Transmembrane Conductance Regulator

Background & Aims Lubiprostone alleviates constipation by stimulating intestinal fluid secretion, purportedly through activation of ClC-2–type Cl− channels. Intestinal obstruction is also a recurrent cause of distress in cystic fibrosis (CF) patients, caused by loss of CF transmembrane conductan...

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Veröffentlicht in:Gastroenterology (New York, N.Y. 1943) N.Y. 1943), 2009-09, Vol.137 (3), p.976-985
Hauptverfasser: Bijvelds, Marcel J.C, Bot, Alice G.M, Escher, Johanna C, de Jonge, Hugo R
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container_issue 3
container_start_page 976
container_title Gastroenterology (New York, N.Y. 1943)
container_volume 137
creator Bijvelds, Marcel J.C
Bot, Alice G.M
Escher, Johanna C
de Jonge, Hugo R
description Background & Aims Lubiprostone alleviates constipation by stimulating intestinal fluid secretion, purportedly through activation of ClC-2–type Cl− channels. Intestinal obstruction is also a recurrent cause of distress in cystic fibrosis (CF) patients, caused by loss of CF transmembrane conductance regulator (CFTR) Cl− channel activity. Because ClC-2 recruitment might be beneficial to CF patients, we investigated lubiprostone's mode of action. Methods Cl− transport was measured in an Ussing chamber, in 3 model systems: (1) T84 colonocytes, (2) intestinal epithelium of wild-type and CF mice, and (3) intestinal epithelium of CF patients and controls. Results In T84 monolayers, lubiprostone induced a robust secretory response. Selective permeabilization of the basolateral plasma membrane revealed that lubiprostone activated an apical Cl− conductance. The lubiprostone response was attenuated by H89, an inhibitor of the cAMP-dependent protein kinase, and lubiprostone precluded responsiveness to the cAMP agonist forskolin. CFTR blockage by CFTRinh172, but not ClC-2 blockage by CdCl2 , inhibited the lubiprostone response. Lubiprostone induced a CdCl2 -insensitive secretory response in mouse intestine, but failed to induce intestinal Cl− secretion in Cftr-null mice. Correspondingly, lubiprostone induced a secretory response in human intestinal epithelium, but not in tissue of CF patients. The EP4 -type prostanoid receptor antagonist L-161,982 blocked the lubiprostone response in all 3 models studied. In T84 cells, lubiprostone induced a rise in cAMP levels that was sensitive to EP4 -receptor blockage. Conclusions Lubiprostone enhances intestinal Cl− and fluid secretion via prostanoid receptor signaling, triggering activation of CFTR. Therefore, it is of limited use for treatment of CF-related intestinal disease.
doi_str_mv 10.1053/j.gastro.2009.05.037
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Intestinal obstruction is also a recurrent cause of distress in cystic fibrosis (CF) patients, caused by loss of CF transmembrane conductance regulator (CFTR) Cl− channel activity. Because ClC-2 recruitment might be beneficial to CF patients, we investigated lubiprostone's mode of action. Methods Cl− transport was measured in an Ussing chamber, in 3 model systems: (1) T84 colonocytes, (2) intestinal epithelium of wild-type and CF mice, and (3) intestinal epithelium of CF patients and controls. Results In T84 monolayers, lubiprostone induced a robust secretory response. Selective permeabilization of the basolateral plasma membrane revealed that lubiprostone activated an apical Cl− conductance. The lubiprostone response was attenuated by H89, an inhibitor of the cAMP-dependent protein kinase, and lubiprostone precluded responsiveness to the cAMP agonist forskolin. CFTR blockage by CFTRinh172, but not ClC-2 blockage by CdCl2 , inhibited the lubiprostone response. Lubiprostone induced a CdCl2 -insensitive secretory response in mouse intestine, but failed to induce intestinal Cl− secretion in Cftr-null mice. Correspondingly, lubiprostone induced a secretory response in human intestinal epithelium, but not in tissue of CF patients. The EP4 -type prostanoid receptor antagonist L-161,982 blocked the lubiprostone response in all 3 models studied. In T84 cells, lubiprostone induced a rise in cAMP levels that was sensitive to EP4 -receptor blockage. Conclusions Lubiprostone enhances intestinal Cl− and fluid secretion via prostanoid receptor signaling, triggering activation of CFTR. Therefore, it is of limited use for treatment of CF-related intestinal disease.</description><identifier>ISSN: 0016-5085</identifier><identifier>EISSN: 1528-0012</identifier><identifier>DOI: 10.1053/j.gastro.2009.05.037</identifier><identifier>PMID: 19454284</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adult ; Alprostadil - analogs &amp; derivatives ; Alprostadil - pharmacology ; Animals ; Carbachol - pharmacology ; Cell Line, Tumor ; Child ; Chloride Channels - metabolism ; Chlorides - metabolism ; Colforsin - pharmacology ; Colon - metabolism ; Cyclic AMP - metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism ; Dose-Response Relationship, Drug ; Gastroenterology and Hepatology ; Humans ; Ileum - metabolism ; Intestinal Mucosa - secretion ; Ion Transport ; Lubiprostone ; Membrane Potentials ; Mice ; Mice, Knockout ; Receptors, Prostaglandin E - antagonists &amp; inhibitors ; Receptors, Prostaglandin E - metabolism ; Receptors, Prostaglandin E, EP2 Subtype ; Tumor Cells, Cultured</subject><ispartof>Gastroenterology (New York, N.Y. 1943), 2009-09, Vol.137 (3), p.976-985</ispartof><rights>AGA Institute</rights><rights>2009 AGA Institute</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c527t-c08e9631443f637dfb7f6092f2525e9c33870c5d884072f306485948f6ce04b93</citedby><cites>FETCH-LOGICAL-c527t-c08e9631443f637dfb7f6092f2525e9c33870c5d884072f306485948f6ce04b93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1053/j.gastro.2009.05.037$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19454284$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bijvelds, Marcel J.C</creatorcontrib><creatorcontrib>Bot, Alice G.M</creatorcontrib><creatorcontrib>Escher, Johanna C</creatorcontrib><creatorcontrib>de Jonge, Hugo R</creatorcontrib><title>Activation of Intestinal Cl− Secretion by Lubiprostone Requires the Cystic Fibrosis Transmembrane Conductance Regulator</title><title>Gastroenterology (New York, N.Y. 1943)</title><addtitle>Gastroenterology</addtitle><description>Background &amp; Aims Lubiprostone alleviates constipation by stimulating intestinal fluid secretion, purportedly through activation of ClC-2–type Cl− channels. Intestinal obstruction is also a recurrent cause of distress in cystic fibrosis (CF) patients, caused by loss of CF transmembrane conductance regulator (CFTR) Cl− channel activity. Because ClC-2 recruitment might be beneficial to CF patients, we investigated lubiprostone's mode of action. Methods Cl− transport was measured in an Ussing chamber, in 3 model systems: (1) T84 colonocytes, (2) intestinal epithelium of wild-type and CF mice, and (3) intestinal epithelium of CF patients and controls. Results In T84 monolayers, lubiprostone induced a robust secretory response. Selective permeabilization of the basolateral plasma membrane revealed that lubiprostone activated an apical Cl− conductance. The lubiprostone response was attenuated by H89, an inhibitor of the cAMP-dependent protein kinase, and lubiprostone precluded responsiveness to the cAMP agonist forskolin. CFTR blockage by CFTRinh172, but not ClC-2 blockage by CdCl2 , inhibited the lubiprostone response. Lubiprostone induced a CdCl2 -insensitive secretory response in mouse intestine, but failed to induce intestinal Cl− secretion in Cftr-null mice. Correspondingly, lubiprostone induced a secretory response in human intestinal epithelium, but not in tissue of CF patients. The EP4 -type prostanoid receptor antagonist L-161,982 blocked the lubiprostone response in all 3 models studied. In T84 cells, lubiprostone induced a rise in cAMP levels that was sensitive to EP4 -receptor blockage. Conclusions Lubiprostone enhances intestinal Cl− and fluid secretion via prostanoid receptor signaling, triggering activation of CFTR. 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Bot, Alice G.M ; Escher, Johanna C ; de Jonge, Hugo R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c527t-c08e9631443f637dfb7f6092f2525e9c33870c5d884072f306485948f6ce04b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adult</topic><topic>Alprostadil - analogs &amp; derivatives</topic><topic>Alprostadil - pharmacology</topic><topic>Animals</topic><topic>Carbachol - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Child</topic><topic>Chloride Channels - metabolism</topic><topic>Chlorides - metabolism</topic><topic>Colforsin - pharmacology</topic><topic>Colon - metabolism</topic><topic>Cyclic AMP - metabolism</topic><topic>Cystic Fibrosis Transmembrane Conductance Regulator - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Gastroenterology and Hepatology</topic><topic>Humans</topic><topic>Ileum - metabolism</topic><topic>Intestinal Mucosa - secretion</topic><topic>Ion Transport</topic><topic>Lubiprostone</topic><topic>Membrane Potentials</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Receptors, Prostaglandin E - antagonists &amp; inhibitors</topic><topic>Receptors, Prostaglandin E - metabolism</topic><topic>Receptors, Prostaglandin E, EP2 Subtype</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bijvelds, Marcel J.C</creatorcontrib><creatorcontrib>Bot, Alice G.M</creatorcontrib><creatorcontrib>Escher, Johanna C</creatorcontrib><creatorcontrib>de Jonge, Hugo R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Gastroenterology (New York, N.Y. 1943)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bijvelds, Marcel J.C</au><au>Bot, Alice G.M</au><au>Escher, Johanna C</au><au>de Jonge, Hugo R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activation of Intestinal Cl− Secretion by Lubiprostone Requires the Cystic Fibrosis Transmembrane Conductance Regulator</atitle><jtitle>Gastroenterology (New York, N.Y. 1943)</jtitle><addtitle>Gastroenterology</addtitle><date>2009-09-01</date><risdate>2009</risdate><volume>137</volume><issue>3</issue><spage>976</spage><epage>985</epage><pages>976-985</pages><issn>0016-5085</issn><eissn>1528-0012</eissn><abstract>Background &amp; Aims Lubiprostone alleviates constipation by stimulating intestinal fluid secretion, purportedly through activation of ClC-2–type Cl− channels. Intestinal obstruction is also a recurrent cause of distress in cystic fibrosis (CF) patients, caused by loss of CF transmembrane conductance regulator (CFTR) Cl− channel activity. Because ClC-2 recruitment might be beneficial to CF patients, we investigated lubiprostone's mode of action. Methods Cl− transport was measured in an Ussing chamber, in 3 model systems: (1) T84 colonocytes, (2) intestinal epithelium of wild-type and CF mice, and (3) intestinal epithelium of CF patients and controls. Results In T84 monolayers, lubiprostone induced a robust secretory response. Selective permeabilization of the basolateral plasma membrane revealed that lubiprostone activated an apical Cl− conductance. The lubiprostone response was attenuated by H89, an inhibitor of the cAMP-dependent protein kinase, and lubiprostone precluded responsiveness to the cAMP agonist forskolin. CFTR blockage by CFTRinh172, but not ClC-2 blockage by CdCl2 , inhibited the lubiprostone response. Lubiprostone induced a CdCl2 -insensitive secretory response in mouse intestine, but failed to induce intestinal Cl− secretion in Cftr-null mice. Correspondingly, lubiprostone induced a secretory response in human intestinal epithelium, but not in tissue of CF patients. The EP4 -type prostanoid receptor antagonist L-161,982 blocked the lubiprostone response in all 3 models studied. In T84 cells, lubiprostone induced a rise in cAMP levels that was sensitive to EP4 -receptor blockage. Conclusions Lubiprostone enhances intestinal Cl− and fluid secretion via prostanoid receptor signaling, triggering activation of CFTR. Therefore, it is of limited use for treatment of CF-related intestinal disease.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19454284</pmid><doi>10.1053/j.gastro.2009.05.037</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
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subjects Adult
Alprostadil - analogs & derivatives
Alprostadil - pharmacology
Animals
Carbachol - pharmacology
Cell Line, Tumor
Child
Chloride Channels - metabolism
Chlorides - metabolism
Colforsin - pharmacology
Colon - metabolism
Cyclic AMP - metabolism
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Dose-Response Relationship, Drug
Gastroenterology and Hepatology
Humans
Ileum - metabolism
Intestinal Mucosa - secretion
Ion Transport
Lubiprostone
Membrane Potentials
Mice
Mice, Knockout
Receptors, Prostaglandin E - antagonists & inhibitors
Receptors, Prostaglandin E - metabolism
Receptors, Prostaglandin E, EP2 Subtype
Tumor Cells, Cultured
title Activation of Intestinal Cl− Secretion by Lubiprostone Requires the Cystic Fibrosis Transmembrane Conductance Regulator
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