OBJECTIVES: 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.
OBJECTIVES: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.
Authors: Daniel R Principe; Brian DeCant; Emman Mascariñas; Elizabeth A Wayne; Andrew M Diaz; Naomi Akagi; Rosa Hwang; Boris Pasche; David W Dawson; Deyu Fang; David J Bentrem; Hidayatullah G Munshi; Barbara Jung; Paul J Grippo Journal: Cancer Res Date: 2016-03-15 Impact factor: 12.701
Authors: Stefan Wildi; Jörg Kleeff; Julia Mayerle; Arthur Zimmermann; Erwin P Böttinger; Lalage Wakefield; Markus W Büchler; Helmut Friess; Murray Korc Journal: Gut Date: 2006-11-29 Impact factor: 23.059
Authors: Xuxia Gao; Yanna Cao; Wenli Yang; Chaojun Duan; Judith F Aronson; Cristiana Rastellini; Celia Chao; Mark R Hellmich; Tien C Ko Journal: Am J Physiol Gastrointest Liver Physiol Date: 2013-02-21 Impact factor: 4.052