The Secretin/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis through Changes in Transforming Growth Factor-β1–Mediated Biliary Senescence
Activation of the secretin (Sct)/secretin receptor (SR) axis stimulates ductular reaction and liver fibrosis, which are hallmarks of cholangiopathies. Our aim was to define the role of Sct-regulated cellular senescence, and we demonstrated that both ductular reaction and liver fibrosis are significa...
Gespeichert in:
| Veröffentlicht in: | The American journal of pathology 2018-10, Vol.188 (10), p.2264-2280 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 2280 |
|---|---|
| container_issue | 10 |
| container_start_page | 2264 |
| container_title | The American journal of pathology |
| container_volume | 188 |
| creator | Wu, Nan Meng, Fanyin Zhou, Tianhao Venter, Julie Giang, Thao K. Kyritsi, Konstantina Wu, Chaodong Alvaro, Domenico Onori, Paolo Mancinelli, Romina Gaudio, Eugenio Francis, Heather Alpini, Gianfranco Glaser, Shannon Franchitto, Antonio |
| description | Activation of the secretin (Sct)/secretin receptor (SR) axis stimulates ductular reaction and liver fibrosis, which are hallmarks of cholangiopathies. Our aim was to define the role of Sct-regulated cellular senescence, and we demonstrated that both ductular reaction and liver fibrosis are significantly reduced in Sct−/−, SR−/−, and Sct−/−/SR−/− bile duct ligated (BDL) mice compared with BDL wild-type mice. The reduction in hepatic fibrosis in Sct−/−, SR−/−, and Sct−/−/SR−/− BDL mice was accompanied by reduced transforming growth factor-β1 levels in serum and cholangiocyte supernatant, as well as decreased expression of markers of cellular senescence in cholangiocytes in contrast to enhanced cellular senescence in hepatic stellate cells compared with BDL wild-type mice. Secretin directly stimulated the senescence of cholangiocytes and regulated, by a paracrine mechanism, the senescence of hepatic stellate cells and liver fibrosis via modulation of transforming growth factor-β1 biliary secretion. Targeting senescent cholangiocytes may represent a novel therapeutic approach for ameliorating hepatic fibrosis during cholestatic liver injury. |
| doi_str_mv | 10.1016/j.ajpath.2018.06.015 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6168967</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0002944018301500</els_id><sourcerecordid>2075548374</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4445-f1c99fb78247dcb3e9915e735cb8435aa82a5f0b3d5b3c91edf8eb00fa2c24e63</originalsourceid><addsrcrecordid>eNp9UUuOEzEQtRCICQM3QMhLNt1jd9v92SANGTKMlBEShLXltqvTjjp2sN0BdtyBG3AEDsIhOMk4yswAG1Yuq16996oeQs8pySmh1dkml5udjENeENrkpMoJ5Q_QjPKCZwVt6UM0I4QUWcsYOUFPQtikb1U25DE6KQkpK16QGfqxGgB_AOUhGnt2V-D3oGAXncfnX0zA105Po4wQ8MWkYip9AkgVjbNYWo2XZg8eL0znXUjwOHg3rQc8H6Rdp6HEt_LSht75rbFrfOnd5zjgRWJwPvv1k_7-9v0atEkKGr82o5H-a_JkISiwCp6iR70cAzy7fU_Rx8Wb1fxttnx3eTU_X2aKMcaznqq27bu6KVitVVdC21IOdclV17CSS9kUkvekKzXvStVS0H0DHSG9LFTBoCpP0asj727qtqCTdvRyFDtvtsmQcNKIfzvWDGLt9qKiVdNWdSJ4eUvg3acJQhRbk1YYR2nBTUEUpOacNWXNEpQdoSqdLHjo72UoEYd4xUYc4xWHeAWpRIo3jb342-L90F2ef3aAdKi9AS-CMocjauNBRaGd-b_CDfY0vq8</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2075548374</pqid></control><display><type>article</type><title>The Secretin/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis through Changes in Transforming Growth Factor-β1–Mediated Biliary Senescence</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Wu, Nan ; Meng, Fanyin ; Zhou, Tianhao ; Venter, Julie ; Giang, Thao K. ; Kyritsi, Konstantina ; Wu, Chaodong ; Alvaro, Domenico ; Onori, Paolo ; Mancinelli, Romina ; Gaudio, Eugenio ; Francis, Heather ; Alpini, Gianfranco ; Glaser, Shannon ; Franchitto, Antonio</creator><creatorcontrib>Wu, Nan ; Meng, Fanyin ; Zhou, Tianhao ; Venter, Julie ; Giang, Thao K. ; Kyritsi, Konstantina ; Wu, Chaodong ; Alvaro, Domenico ; Onori, Paolo ; Mancinelli, Romina ; Gaudio, Eugenio ; Francis, Heather ; Alpini, Gianfranco ; Glaser, Shannon ; Franchitto, Antonio</creatorcontrib><description>Activation of the secretin (Sct)/secretin receptor (SR) axis stimulates ductular reaction and liver fibrosis, which are hallmarks of cholangiopathies. Our aim was to define the role of Sct-regulated cellular senescence, and we demonstrated that both ductular reaction and liver fibrosis are significantly reduced in Sct−/−, SR−/−, and Sct−/−/SR−/− bile duct ligated (BDL) mice compared with BDL wild-type mice. The reduction in hepatic fibrosis in Sct−/−, SR−/−, and Sct−/−/SR−/− BDL mice was accompanied by reduced transforming growth factor-β1 levels in serum and cholangiocyte supernatant, as well as decreased expression of markers of cellular senescence in cholangiocytes in contrast to enhanced cellular senescence in hepatic stellate cells compared with BDL wild-type mice. Secretin directly stimulated the senescence of cholangiocytes and regulated, by a paracrine mechanism, the senescence of hepatic stellate cells and liver fibrosis via modulation of transforming growth factor-β1 biliary secretion. Targeting senescent cholangiocytes may represent a novel therapeutic approach for ameliorating hepatic fibrosis during cholestatic liver injury.</description><identifier>ISSN: 0002-9440</identifier><identifier>EISSN: 1525-2191</identifier><identifier>DOI: 10.1016/j.ajpath.2018.06.015</identifier><identifier>PMID: 30036520</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Bile Ducts - cytology ; Cellular Senescence - physiology ; Kupffer Cells - metabolism ; Liver Cirrhosis - physiopathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Organ Size ; Receptors, G-Protein-Coupled - physiology ; Receptors, Gastrointestinal Hormone - physiology ; RNA, Messenger - metabolism ; Secretin - metabolism ; Secretin - pharmacology ; Transforming Growth Factor beta1 - physiology</subject><ispartof>The American journal of pathology, 2018-10, Vol.188 (10), p.2264-2280</ispartof><rights>2018 American Society for Investigative Pathology</rights><rights>Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.</rights><rights>2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. 2018 American Society for Investigative Pathology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4445-f1c99fb78247dcb3e9915e735cb8435aa82a5f0b3d5b3c91edf8eb00fa2c24e63</citedby><cites>FETCH-LOGICAL-c4445-f1c99fb78247dcb3e9915e735cb8435aa82a5f0b3d5b3c91edf8eb00fa2c24e63</cites><orcidid>0000-0003-2040-0581 ; 0000-0002-7195-3760 ; 0000-0003-3771-9644</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168967/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ajpath.2018.06.015$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,724,777,781,882,3537,27905,27906,45976,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30036520$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Nan</creatorcontrib><creatorcontrib>Meng, Fanyin</creatorcontrib><creatorcontrib>Zhou, Tianhao</creatorcontrib><creatorcontrib>Venter, Julie</creatorcontrib><creatorcontrib>Giang, Thao K.</creatorcontrib><creatorcontrib>Kyritsi, Konstantina</creatorcontrib><creatorcontrib>Wu, Chaodong</creatorcontrib><creatorcontrib>Alvaro, Domenico</creatorcontrib><creatorcontrib>Onori, Paolo</creatorcontrib><creatorcontrib>Mancinelli, Romina</creatorcontrib><creatorcontrib>Gaudio, Eugenio</creatorcontrib><creatorcontrib>Francis, Heather</creatorcontrib><creatorcontrib>Alpini, Gianfranco</creatorcontrib><creatorcontrib>Glaser, Shannon</creatorcontrib><creatorcontrib>Franchitto, Antonio</creatorcontrib><title>The Secretin/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis through Changes in Transforming Growth Factor-β1–Mediated Biliary Senescence</title><title>The American journal of pathology</title><addtitle>Am J Pathol</addtitle><description>Activation of the secretin (Sct)/secretin receptor (SR) axis stimulates ductular reaction and liver fibrosis, which are hallmarks of cholangiopathies. Our aim was to define the role of Sct-regulated cellular senescence, and we demonstrated that both ductular reaction and liver fibrosis are significantly reduced in Sct−/−, SR−/−, and Sct−/−/SR−/− bile duct ligated (BDL) mice compared with BDL wild-type mice. The reduction in hepatic fibrosis in Sct−/−, SR−/−, and Sct−/−/SR−/− BDL mice was accompanied by reduced transforming growth factor-β1 levels in serum and cholangiocyte supernatant, as well as decreased expression of markers of cellular senescence in cholangiocytes in contrast to enhanced cellular senescence in hepatic stellate cells compared with BDL wild-type mice. Secretin directly stimulated the senescence of cholangiocytes and regulated, by a paracrine mechanism, the senescence of hepatic stellate cells and liver fibrosis via modulation of transforming growth factor-β1 biliary secretion. Targeting senescent cholangiocytes may represent a novel therapeutic approach for ameliorating hepatic fibrosis during cholestatic liver injury.</description><subject>Animals</subject><subject>Bile Ducts - cytology</subject><subject>Cellular Senescence - physiology</subject><subject>Kupffer Cells - metabolism</subject><subject>Liver Cirrhosis - physiopathology</subject><subject>Male</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Organ Size</subject><subject>Receptors, G-Protein-Coupled - physiology</subject><subject>Receptors, Gastrointestinal Hormone - physiology</subject><subject>RNA, Messenger - metabolism</subject><subject>Secretin - metabolism</subject><subject>Secretin - pharmacology</subject><subject>Transforming Growth Factor beta1 - physiology</subject><issn>0002-9440</issn><issn>1525-2191</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UUuOEzEQtRCICQM3QMhLNt1jd9v92SANGTKMlBEShLXltqvTjjp2sN0BdtyBG3AEDsIhOMk4yswAG1Yuq16996oeQs8pySmh1dkml5udjENeENrkpMoJ5Q_QjPKCZwVt6UM0I4QUWcsYOUFPQtikb1U25DE6KQkpK16QGfqxGgB_AOUhGnt2V-D3oGAXncfnX0zA105Po4wQ8MWkYip9AkgVjbNYWo2XZg8eL0znXUjwOHg3rQc8H6Rdp6HEt_LSht75rbFrfOnd5zjgRWJwPvv1k_7-9v0atEkKGr82o5H-a_JkISiwCp6iR70cAzy7fU_Rx8Wb1fxttnx3eTU_X2aKMcaznqq27bu6KVitVVdC21IOdclV17CSS9kUkvekKzXvStVS0H0DHSG9LFTBoCpP0asj727qtqCTdvRyFDtvtsmQcNKIfzvWDGLt9qKiVdNWdSJ4eUvg3acJQhRbk1YYR2nBTUEUpOacNWXNEpQdoSqdLHjo72UoEYd4xUYc4xWHeAWpRIo3jb342-L90F2ef3aAdKi9AS-CMocjauNBRaGd-b_CDfY0vq8</recordid><startdate>201810</startdate><enddate>201810</enddate><creator>Wu, Nan</creator><creator>Meng, Fanyin</creator><creator>Zhou, Tianhao</creator><creator>Venter, Julie</creator><creator>Giang, Thao K.</creator><creator>Kyritsi, Konstantina</creator><creator>Wu, Chaodong</creator><creator>Alvaro, Domenico</creator><creator>Onori, Paolo</creator><creator>Mancinelli, Romina</creator><creator>Gaudio, Eugenio</creator><creator>Francis, Heather</creator><creator>Alpini, Gianfranco</creator><creator>Glaser, Shannon</creator><creator>Franchitto, Antonio</creator><general>Elsevier Inc</general><general>American Society for Investigative Pathology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2040-0581</orcidid><orcidid>https://orcid.org/0000-0002-7195-3760</orcidid><orcidid>https://orcid.org/0000-0003-3771-9644</orcidid></search><sort><creationdate>201810</creationdate><title>The Secretin/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis through Changes in Transforming Growth Factor-β1–Mediated Biliary Senescence</title><author>Wu, Nan ; Meng, Fanyin ; Zhou, Tianhao ; Venter, Julie ; Giang, Thao K. ; Kyritsi, Konstantina ; Wu, Chaodong ; Alvaro, Domenico ; Onori, Paolo ; Mancinelli, Romina ; Gaudio, Eugenio ; Francis, Heather ; Alpini, Gianfranco ; Glaser, Shannon ; Franchitto, Antonio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4445-f1c99fb78247dcb3e9915e735cb8435aa82a5f0b3d5b3c91edf8eb00fa2c24e63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Bile Ducts - cytology</topic><topic>Cellular Senescence - physiology</topic><topic>Kupffer Cells - metabolism</topic><topic>Liver Cirrhosis - physiopathology</topic><topic>Male</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Organ Size</topic><topic>Receptors, G-Protein-Coupled - physiology</topic><topic>Receptors, Gastrointestinal Hormone - physiology</topic><topic>RNA, Messenger - metabolism</topic><topic>Secretin - metabolism</topic><topic>Secretin - pharmacology</topic><topic>Transforming Growth Factor beta1 - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Nan</creatorcontrib><creatorcontrib>Meng, Fanyin</creatorcontrib><creatorcontrib>Zhou, Tianhao</creatorcontrib><creatorcontrib>Venter, Julie</creatorcontrib><creatorcontrib>Giang, Thao K.</creatorcontrib><creatorcontrib>Kyritsi, Konstantina</creatorcontrib><creatorcontrib>Wu, Chaodong</creatorcontrib><creatorcontrib>Alvaro, Domenico</creatorcontrib><creatorcontrib>Onori, Paolo</creatorcontrib><creatorcontrib>Mancinelli, Romina</creatorcontrib><creatorcontrib>Gaudio, Eugenio</creatorcontrib><creatorcontrib>Francis, Heather</creatorcontrib><creatorcontrib>Alpini, Gianfranco</creatorcontrib><creatorcontrib>Glaser, Shannon</creatorcontrib><creatorcontrib>Franchitto, Antonio</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>The American journal of pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Nan</au><au>Meng, Fanyin</au><au>Zhou, Tianhao</au><au>Venter, Julie</au><au>Giang, Thao K.</au><au>Kyritsi, Konstantina</au><au>Wu, Chaodong</au><au>Alvaro, Domenico</au><au>Onori, Paolo</au><au>Mancinelli, Romina</au><au>Gaudio, Eugenio</au><au>Francis, Heather</au><au>Alpini, Gianfranco</au><au>Glaser, Shannon</au><au>Franchitto, Antonio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Secretin/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis through Changes in Transforming Growth Factor-β1–Mediated Biliary Senescence</atitle><jtitle>The American journal of pathology</jtitle><addtitle>Am J Pathol</addtitle><date>2018-10</date><risdate>2018</risdate><volume>188</volume><issue>10</issue><spage>2264</spage><epage>2280</epage><pages>2264-2280</pages><issn>0002-9440</issn><eissn>1525-2191</eissn><abstract>Activation of the secretin (Sct)/secretin receptor (SR) axis stimulates ductular reaction and liver fibrosis, which are hallmarks of cholangiopathies. Our aim was to define the role of Sct-regulated cellular senescence, and we demonstrated that both ductular reaction and liver fibrosis are significantly reduced in Sct−/−, SR−/−, and Sct−/−/SR−/− bile duct ligated (BDL) mice compared with BDL wild-type mice. The reduction in hepatic fibrosis in Sct−/−, SR−/−, and Sct−/−/SR−/− BDL mice was accompanied by reduced transforming growth factor-β1 levels in serum and cholangiocyte supernatant, as well as decreased expression of markers of cellular senescence in cholangiocytes in contrast to enhanced cellular senescence in hepatic stellate cells compared with BDL wild-type mice. Secretin directly stimulated the senescence of cholangiocytes and regulated, by a paracrine mechanism, the senescence of hepatic stellate cells and liver fibrosis via modulation of transforming growth factor-β1 biliary secretion. Targeting senescent cholangiocytes may represent a novel therapeutic approach for ameliorating hepatic fibrosis during cholestatic liver injury.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30036520</pmid><doi>10.1016/j.ajpath.2018.06.015</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0003-2040-0581</orcidid><orcidid>https://orcid.org/0000-0002-7195-3760</orcidid><orcidid>https://orcid.org/0000-0003-3771-9644</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0002-9440 |
| ispartof | The American journal of pathology, 2018-10, Vol.188 (10), p.2264-2280 |
| issn | 0002-9440 1525-2191 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6168967 |
| source | MEDLINE; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals Bile Ducts - cytology Cellular Senescence - physiology Kupffer Cells - metabolism Liver Cirrhosis - physiopathology Male Mice, Inbred C57BL Mice, Knockout Organ Size Receptors, G-Protein-Coupled - physiology Receptors, Gastrointestinal Hormone - physiology RNA, Messenger - metabolism Secretin - metabolism Secretin - pharmacology Transforming Growth Factor beta1 - physiology |
| title | The Secretin/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis through Changes in Transforming Growth Factor-β1–Mediated Biliary Senescence |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-21T04%3A04%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20Secretin/Secretin%20Receptor%20Axis%20Modulates%20Ductular%20Reaction%20and%20Liver%20Fibrosis%20through%20Changes%20in%20Transforming%20Growth%20Factor-%CE%B21%E2%80%93Mediated%20Biliary%20Senescence&rft.jtitle=The%20American%20journal%20of%20pathology&rft.au=Wu,%20Nan&rft.date=2018-10&rft.volume=188&rft.issue=10&rft.spage=2264&rft.epage=2280&rft.pages=2264-2280&rft.issn=0002-9440&rft.eissn=1525-2191&rft_id=info:doi/10.1016/j.ajpath.2018.06.015&rft_dat=%3Cproquest_pubme%3E2075548374%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2075548374&rft_id=info:pmid/30036520&rft_els_id=S0002944018301500&rfr_iscdi=true |