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Amelioration of pancreatic fibrosis in mice with defective TGF-beta signaling.

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dc.contributor.authorYoo, BM-
dc.contributor.authorYeo, M-
dc.contributor.authorOh, TY-
dc.contributor.authorChoi, JH-
dc.contributor.authorKim, WW-
dc.contributor.authorKim, JH-
dc.contributor.authorCho, SW-
dc.contributor.authorKim, SJ-
dc.contributor.authorHahm, KB-
dc.date.accessioned2011-07-08T04:49:28Z-
dc.date.available2011-07-08T04:49:28Z-
dc.date.issued2005-
dc.identifier.issn0885-3177-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/3261-
dc.description.abstractOBJECTIVES: Pancreatic fibrosis is a characteristic feature of chronic pancreatic injury, which is a result of the imbalance between synthesis and degradation of extracellular matrix (ECM) proteins. Transforming growth factor-beta (TGF-beta) plays a central role in biosynthesis and turnover of the ECM. In this study, we evaluated the role of TGF-beta signaling in pancreatic fibrosis induced by repetitive acute pancreatic injuries with mice of dominant-negative mutant of TGF-beta receptor II selectively in pancreas.



METHODS: TGF-beta signaling was inactivated by overexpressing a dominant-negative mutant form of TGF-beta type II receptor (pS2-dnR II) only in the pancreas under control of pS2/TFF1 promoter. Pancreatic fibrosis was induced by repeated intraperitoneal injections of 40 microg/kg cerulein for 5 or 10 weeks.



RESULTS: Repeated administration of cerulein induced significant pancreatic fibrosis, but of which fibrosis was remarkably attenuated in pS2-dnR II mice compared with wild-type littermates (P < 0.01). The ameliorated fibrosis was due to the reduction of synthesis of ECM proteins such as collagen type I, fibronectin, and ICAM-1. DNA binding activity of transcriptional factors including nuclear factor (NF)-kappaB and AP-1, responsible for the induction of immediate early genes of inflammatory responses, were significantly decreased in pS2-dnR II mice. While TGF-beta1 treatment in isolated pancreatic stellate cells (PSCs) stimulated the expression of alpha-SMA and fibronectin, PSCs transfected with TGF-beta dnRII showed attenuation of the ECM components.



CONCLUSION: Conditional loss of TGF-beta signaling selectively in the pancreas led to a failure in fibrogenic responses of repeated injections of cerulein, signifying that the modulation of TGF-beta signaling could be the therapeutic target for the prevention of chronic fibrosing pancreatitis.
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dc.language.isoen-
dc.subject.MESHAnimals-
dc.subject.MESHCaerulein-
dc.subject.MESHCells, Cultured-
dc.subject.MESHExtracellular Matrix Proteins-
dc.subject.MESHFibrosis-
dc.subject.MESHMale-
dc.subject.MESHMice-
dc.subject.MESHMice, Inbred Strains-
dc.subject.MESHMice, Transgenic-
dc.subject.MESHNF-kappa B-
dc.subject.MESHPancreas-
dc.subject.MESHPancreatitis, Chronic-
dc.subject.MESHProtein-Serine-Threonine Kinases-
dc.subject.MESHReceptors, Transforming Growth Factor beta-
dc.subject.MESHSignal Transduction-
dc.subject.MESHTranscription Factor AP-1-
dc.subject.MESHTranscription, Genetic-
dc.subject.MESHTransfection-
dc.subject.MESHTransforming Growth Factor beta-
dc.subject.MESHTransforming Growth Factor beta1-
dc.titleAmelioration of pancreatic fibrosis in mice with defective TGF-beta signaling.-
dc.typeArticle-
dc.identifier.pmid15782092-
dc.identifier.urlhttp://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0885-3177&volume=30&issue=3&spage=e71-
dc.contributor.affiliatedAuthor유, 병무-
dc.contributor.affiliatedAuthor여, 말희-
dc.contributor.affiliatedAuthor최, 준혁-
dc.contributor.affiliatedAuthor김, 욱환-
dc.contributor.affiliatedAuthor김, 진홍-
dc.contributor.affiliatedAuthor조, 성원-
dc.contributor.affiliatedAuthor함, 기백-
dc.type.localJournal Papers-
dc.citation.titlePancreas-
dc.citation.volume30-
dc.citation.number3-
dc.citation.date2005-
dc.citation.startPagee71-
dc.citation.endPagee79-
dc.identifier.bibliographicCitationPancreas, 30(3). : e71-e79, 2005-
dc.identifier.eissn1536-4828-
dc.relation.journalidJ008853177-
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Gastroenterology
Journal Papers > Research Organization > Genomic Research Center for Gastroenterology
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
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