title: Retinoic Acid Ameliorates Pancreatic Fibrosis and Inhibits the Activation of Pancreatic Stellate Cells in Mice with Experimental Chronic Pancreatitis via Suppressing the Wnt/β-Catenin Signaling Pathway.
abstract: Pancreatic fibrosis, a prominent feature of chronic pancreatitis (CP), induces persistent and permanent damage in the pancreas. Pancreatic stellate cells (PSCs) provide a major source of extracellular matrix (ECM) deposition during pancreatic injury, and persistent activation of PSCs plays a vital role in the progression of pancreatic fibrosis. Retinoic acid (RA), a retinoid, has a broad range of biological functions, including regulation of cell differentiation and proliferation, attenuating progressive fibrosis of multiple organs. In the present study, we investigated the effects of RA on fibrosis in experimental CP and cultured PSCs. CP was induced in mice by repetitive cerulein injection in vivo, and mouse PSCs were isolated and activated in vitro. Suppression of pancreatic fibrosis upon administration of RA was confirmed based on reduction of histological damage, α-smooth muscle actin (α-SMA) expression and mRNA levels of β-catenin, platelet-derived growth factor (PDGF)-Rβ transforming growth factor (TGF)-βRII and collagen 1α1 in vivo. Wnt 2 and β-catenin protein levels were markedly down-regulated, while Axin 2 expression level was up-regulated in the presence of RA, both in vivo and in vitro. Nuclear translation of β-catenin was significantly decreased following RA treatment, compared with cerulein-induced CP in mice and activated PSCs. Furthermore, RA induced significant PSC apoptosis, inhibited proliferation, suppressed TCF/LEF-dependent transcriptional activity and ECM production of PSC via down-regulation of TGFβRII, PDGFRβ and collagen 1α1 in vitro. These results indicate a critical role of the Wnt/β-catenin signaling pathway in RA-induced effects on CP and PSC regulation and support the potential of RA as a suppressor of pancreatic fibrosis in mice.
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Wenqin
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterology, Shanghai Changzheng Hospital, Shanghai Second Military Medical University, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Guojian
authors.initials: G
authors.lastname: Yin
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Deqing
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Xing
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Guoyong
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Xingpeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.|Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wan
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D060466:Axin Protein / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D002108:Ceruletide / Q000633:toxicity; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000187:drug effects; D008049:Lipase / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D055292:Pancreatic alpha-Amylases / Q000097:blood; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D000199:Actins; D060466:Axin Protein; C111729:Axin2 protein, mouse; D024042:Collagen Type I; D011509:Proteoglycans; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C544013:alpha-smooth muscle actin, mouse; C071736:betaglycan; D014212:Tretinoin; D002108:Ceruletide; D020797:Receptor, Platelet-Derived Growth Factor beta; D008049:Lipase; D055292:Pancreatic alpha-Amylases