TGF-β2 silencing to target biliary-derived liver diseases
ObjectiveTGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in bilia...
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| Veröffentlicht in: | Gut 2020-09, Vol.69 (9), p.1677-1690 |
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| creator | Dropmann, Anne Dooley, Steven Dewidar, Bedair Hammad, Seddik Dediulia, Tatjana Werle, Julia Hartwig, Vanessa Ghafoory, Shahrouz Woelfl, Stefan Korhonen, Hanna Janicot, Michel Wosikowski, Katja Itzel, Timo Teufel, Andreas Schuppan, Detlef Stojanovic, Ana Cerwenka, Adelheid Nittka, Stefanie Piiper, Albrecht Gaiser, Timo Beraza, Naiara Milkiewicz, Malgorzata Milkiewicz, Piotr Brain, John G Jones, David E J Weiss, Thomas S Zanger, Ulrich M Ebert, Matthias Meindl-Beinker, Nadja M |
| description | ObjectiveTGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.DesignAs we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.Results TgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.ConclusionsTaken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development. |
| doi_str_mv | 10.1136/gutjnl-2019-319091 |
| format | Article |
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Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.DesignAs we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.Results TgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.ConclusionsTaken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.</description><identifier>ISSN: 0017-5749</identifier><identifier>EISSN: 1468-3288</identifier><identifier>DOI: 10.1136/gutjnl-2019-319091</identifier><identifier>PMID: 31992593</identifier><language>eng</language><publisher>England: BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><subject>Animal models ; Animals ; Antisense oligonucleotides ; ATP Binding Cassette Transporter, Subfamily B - genetics ; ATP-Binding Cassette Sub-Family B Member 4 ; Bile ; Bile ducts ; CCL3 protein ; CD45 antigen ; Cholangitis ; Cholangitis, Sclerosing - metabolism ; Cholangitis, Sclerosing - pathology ; cholestasis ; Clinical trials ; Collagen ; Disease Models, Animal ; Drug development ; Drug Discovery ; fibrosis ; Gene Expression Regulation ; Gene Silencing ; Growth factors ; Hepatic Stellate Cells - metabolism ; Hepatology ; Humans ; Hydroxyproline ; Inflammation ; Leukocytes (eosinophilic) ; Liver cancer ; Liver Cirrhosis - metabolism ; Liver Cirrhosis - pathology ; Liver Cirrhosis - prevention & control ; Liver Cirrhosis, Biliary - metabolism ; Liver Cirrhosis, Biliary - pathology ; Liver diseases ; Mice ; Mice, Knockout ; Oligonucleotides, Antisense ; Patients ; Peroxisome proliferator-activated receptors ; primary biliary cirrhosis ; primary sclerosing cholangitis ; TGF-beta ; Transforming Growth Factor beta2 - genetics ; Transforming Growth Factor beta2 - metabolism ; Transforming growth factor-b ; Transforming growth factor-b1 ; Up-Regulation</subject><ispartof>Gut, 2020-09, Vol.69 (9), p.1677-1690</ispartof><rights>Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2020 Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b4221-6141d4311661c61307b4478cc2834159aea8360706ba37eca48eaa466ff841803</citedby><cites>FETCH-LOGICAL-b4221-6141d4311661c61307b4478cc2834159aea8360706ba37eca48eaa466ff841803</cites><orcidid>0000-0002-6022-073X ; 0000-0003-0211-352X ; 0000-0003-3135-1359 ; 0000-0002-4840-6240 ; 0000-0003-0336-0581 ; 0000-0001-7953-8927</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/PMC7456737/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456737/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31992593$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dropmann, Anne</creatorcontrib><creatorcontrib>Dooley, Steven</creatorcontrib><creatorcontrib>Dewidar, Bedair</creatorcontrib><creatorcontrib>Hammad, Seddik</creatorcontrib><creatorcontrib>Dediulia, Tatjana</creatorcontrib><creatorcontrib>Werle, Julia</creatorcontrib><creatorcontrib>Hartwig, Vanessa</creatorcontrib><creatorcontrib>Ghafoory, Shahrouz</creatorcontrib><creatorcontrib>Woelfl, Stefan</creatorcontrib><creatorcontrib>Korhonen, Hanna</creatorcontrib><creatorcontrib>Janicot, Michel</creatorcontrib><creatorcontrib>Wosikowski, Katja</creatorcontrib><creatorcontrib>Itzel, Timo</creatorcontrib><creatorcontrib>Teufel, Andreas</creatorcontrib><creatorcontrib>Schuppan, Detlef</creatorcontrib><creatorcontrib>Stojanovic, Ana</creatorcontrib><creatorcontrib>Cerwenka, Adelheid</creatorcontrib><creatorcontrib>Nittka, Stefanie</creatorcontrib><creatorcontrib>Piiper, Albrecht</creatorcontrib><creatorcontrib>Gaiser, Timo</creatorcontrib><creatorcontrib>Beraza, Naiara</creatorcontrib><creatorcontrib>Milkiewicz, Malgorzata</creatorcontrib><creatorcontrib>Milkiewicz, Piotr</creatorcontrib><creatorcontrib>Brain, John G</creatorcontrib><creatorcontrib>Jones, David E J</creatorcontrib><creatorcontrib>Weiss, Thomas S</creatorcontrib><creatorcontrib>Zanger, Ulrich M</creatorcontrib><creatorcontrib>Ebert, Matthias</creatorcontrib><creatorcontrib>Meindl-Beinker, Nadja M</creatorcontrib><title>TGF-β2 silencing to target biliary-derived liver diseases</title><title>Gut</title><addtitle>Gut</addtitle><addtitle>Gut</addtitle><description>ObjectiveTGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.DesignAs we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.Results TgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.ConclusionsTaken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.</description><subject>Animal models</subject><subject>Animals</subject><subject>Antisense oligonucleotides</subject><subject>ATP Binding Cassette Transporter, Subfamily B - genetics</subject><subject>ATP-Binding Cassette Sub-Family B Member 4</subject><subject>Bile</subject><subject>Bile ducts</subject><subject>CCL3 protein</subject><subject>CD45 antigen</subject><subject>Cholangitis</subject><subject>Cholangitis, Sclerosing - metabolism</subject><subject>Cholangitis, Sclerosing - pathology</subject><subject>cholestasis</subject><subject>Clinical trials</subject><subject>Collagen</subject><subject>Disease Models, Animal</subject><subject>Drug development</subject><subject>Drug Discovery</subject><subject>fibrosis</subject><subject>Gene Expression Regulation</subject><subject>Gene Silencing</subject><subject>Growth factors</subject><subject>Hepatic Stellate Cells - metabolism</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Hydroxyproline</subject><subject>Inflammation</subject><subject>Leukocytes (eosinophilic)</subject><subject>Liver cancer</subject><subject>Liver Cirrhosis - metabolism</subject><subject>Liver Cirrhosis - pathology</subject><subject>Liver Cirrhosis - prevention & control</subject><subject>Liver Cirrhosis, Biliary - metabolism</subject><subject>Liver Cirrhosis, Biliary - pathology</subject><subject>Liver diseases</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Oligonucleotides, Antisense</subject><subject>Patients</subject><subject>Peroxisome proliferator-activated receptors</subject><subject>primary biliary cirrhosis</subject><subject>primary sclerosing cholangitis</subject><subject>TGF-beta</subject><subject>Transforming Growth Factor beta2 - genetics</subject><subject>Transforming Growth Factor beta2 - metabolism</subject><subject>Transforming growth factor-b</subject><subject>Transforming growth factor-b1</subject><subject>Up-Regulation</subject><issn>0017-5749</issn><issn>1468-3288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>9YT</sourceid><sourceid>ACMMV</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkMFKwzAcxoMobk5fwIMUPGfmn6RJ6kGQ4aYw8DLPIW2zmdK1M2kFX8sH8Zns6Jx6ES_JIb_vy8cPoXMgYwAmrlZtU1QlpgQSzCAhCRygIXChMKNKHaIhISBxLHkyQCchFIQQpRI4RoOOTmicsCG6Xsym-OOdRsGVtspctYqaOmqMX9kmSl3pjH_DufXu1eZR2Z0-yl2wJthwio6Wpgz2bHeP0NP0bjG5x_PH2cPkdo5TTilgARxyzgCEgEwAIzLlXKoso4pxiBNjjWKCSCJSw6TNDFfWGC7Ecqk4KMJG6Kbv3bTp2uaZrRpvSr3xbt2N07Vx-vdL5Z71qn7VksdCMtkVXO4KfP3S2tDoom591W3WlDPKeEyJ6ijaU5mvQ_B2uf8BiN761r1vvfWte99d6OLntn3kS3AH4B5I18X_Csff_H7mH4FPGxCZlA</recordid><startdate>20200901</startdate><enddate>20200901</enddate><creator>Dropmann, Anne</creator><creator>Dooley, Steven</creator><creator>Dewidar, Bedair</creator><creator>Hammad, Seddik</creator><creator>Dediulia, 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silencing to target biliary-derived liver diseases</title><author>Dropmann, Anne ; Dooley, Steven ; Dewidar, Bedair ; Hammad, Seddik ; Dediulia, Tatjana ; Werle, Julia ; Hartwig, Vanessa ; Ghafoory, Shahrouz ; Woelfl, Stefan ; Korhonen, Hanna ; Janicot, Michel ; Wosikowski, Katja ; Itzel, Timo ; Teufel, Andreas ; Schuppan, Detlef ; Stojanovic, Ana ; Cerwenka, Adelheid ; Nittka, Stefanie ; Piiper, Albrecht ; Gaiser, Timo ; Beraza, Naiara ; Milkiewicz, Malgorzata ; Milkiewicz, Piotr ; Brain, John G ; Jones, David E J ; Weiss, Thomas S ; Zanger, Ulrich M ; Ebert, Matthias ; Meindl-Beinker, Nadja M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b4221-6141d4311661c61307b4478cc2834159aea8360706ba37eca48eaa466ff841803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Antisense oligonucleotides</topic><topic>ATP Binding Cassette Transporter, Subfamily B - genetics</topic><topic>ATP-Binding Cassette Sub-Family B Member 4</topic><topic>Bile</topic><topic>Bile ducts</topic><topic>CCL3 protein</topic><topic>CD45 antigen</topic><topic>Cholangitis</topic><topic>Cholangitis, Sclerosing - metabolism</topic><topic>Cholangitis, Sclerosing - pathology</topic><topic>cholestasis</topic><topic>Clinical trials</topic><topic>Collagen</topic><topic>Disease Models, Animal</topic><topic>Drug development</topic><topic>Drug Discovery</topic><topic>fibrosis</topic><topic>Gene Expression Regulation</topic><topic>Gene Silencing</topic><topic>Growth factors</topic><topic>Hepatic Stellate Cells - metabolism</topic><topic>Hepatology</topic><topic>Humans</topic><topic>Hydroxyproline</topic><topic>Inflammation</topic><topic>Leukocytes (eosinophilic)</topic><topic>Liver cancer</topic><topic>Liver Cirrhosis - metabolism</topic><topic>Liver Cirrhosis - pathology</topic><topic>Liver Cirrhosis - prevention & control</topic><topic>Liver Cirrhosis, Biliary - metabolism</topic><topic>Liver Cirrhosis, Biliary - pathology</topic><topic>Liver diseases</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Oligonucleotides, Antisense</topic><topic>Patients</topic><topic>Peroxisome proliferator-activated receptors</topic><topic>primary biliary cirrhosis</topic><topic>primary sclerosing cholangitis</topic><topic>TGF-beta</topic><topic>Transforming Growth Factor beta2 - genetics</topic><topic>Transforming Growth Factor beta2 - metabolism</topic><topic>Transforming growth factor-b</topic><topic>Transforming growth factor-b1</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dropmann, Anne</creatorcontrib><creatorcontrib>Dooley, Steven</creatorcontrib><creatorcontrib>Dewidar, Bedair</creatorcontrib><creatorcontrib>Hammad, Seddik</creatorcontrib><creatorcontrib>Dediulia, Tatjana</creatorcontrib><creatorcontrib>Werle, 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Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Gut</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dropmann, Anne</au><au>Dooley, Steven</au><au>Dewidar, Bedair</au><au>Hammad, Seddik</au><au>Dediulia, Tatjana</au><au>Werle, Julia</au><au>Hartwig, Vanessa</au><au>Ghafoory, Shahrouz</au><au>Woelfl, Stefan</au><au>Korhonen, Hanna</au><au>Janicot, Michel</au><au>Wosikowski, Katja</au><au>Itzel, Timo</au><au>Teufel, Andreas</au><au>Schuppan, Detlef</au><au>Stojanovic, Ana</au><au>Cerwenka, Adelheid</au><au>Nittka, Stefanie</au><au>Piiper, Albrecht</au><au>Gaiser, Timo</au><au>Beraza, Naiara</au><au>Milkiewicz, Malgorzata</au><au>Milkiewicz, Piotr</au><au>Brain, John G</au><au>Jones, David E J</au><au>Weiss, Thomas S</au><au>Zanger, Ulrich M</au><au>Ebert, Matthias</au><au>Meindl-Beinker, Nadja M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TGF-β2 silencing to target biliary-derived liver diseases</atitle><jtitle>Gut</jtitle><stitle>Gut</stitle><addtitle>Gut</addtitle><date>2020-09-01</date><risdate>2020</risdate><volume>69</volume><issue>9</issue><spage>1677</spage><epage>1690</epage><pages>1677-1690</pages><issn>0017-5749</issn><eissn>1468-3288</eissn><abstract>ObjectiveTGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.DesignAs we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.Results TgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.ConclusionsTaken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.</abstract><cop>England</cop><pub>BMJ Publishing Group Ltd and British Society of Gastroenterology</pub><pmid>31992593</pmid><doi>10.1136/gutjnl-2019-319091</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-6022-073X</orcidid><orcidid>https://orcid.org/0000-0003-0211-352X</orcidid><orcidid>https://orcid.org/0000-0003-3135-1359</orcidid><orcidid>https://orcid.org/0000-0002-4840-6240</orcidid><orcidid>https://orcid.org/0000-0003-0336-0581</orcidid><orcidid>https://orcid.org/0000-0001-7953-8927</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0017-5749 |
| ispartof | Gut, 2020-09, Vol.69 (9), p.1677-1690 |
| issn | 0017-5749 1468-3288 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7456737 |
| source | MEDLINE; PubMed Central |
| subjects | Animal models Animals Antisense oligonucleotides ATP Binding Cassette Transporter, Subfamily B - genetics ATP-Binding Cassette Sub-Family B Member 4 Bile Bile ducts CCL3 protein CD45 antigen Cholangitis Cholangitis, Sclerosing - metabolism Cholangitis, Sclerosing - pathology cholestasis Clinical trials Collagen Disease Models, Animal Drug development Drug Discovery fibrosis Gene Expression Regulation Gene Silencing Growth factors Hepatic Stellate Cells - metabolism Hepatology Humans Hydroxyproline Inflammation Leukocytes (eosinophilic) Liver cancer Liver Cirrhosis - metabolism Liver Cirrhosis - pathology Liver Cirrhosis - prevention & control Liver Cirrhosis, Biliary - metabolism Liver Cirrhosis, Biliary - pathology Liver diseases Mice Mice, Knockout Oligonucleotides, Antisense Patients Peroxisome proliferator-activated receptors primary biliary cirrhosis primary sclerosing cholangitis TGF-beta Transforming Growth Factor beta2 - genetics Transforming Growth Factor beta2 - metabolism Transforming growth factor-b Transforming growth factor-b1 Up-Regulation |
| title | TGF-β2 silencing to target biliary-derived liver diseases |
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