title: Pigment epithelium-derived factor regulates early pancreatic fibrotic responses and suppresses the profibrotic cytokine thrombospondin-1.
abstract: Pigment epithelium-derived factor (PEDF) is important for maintaining the normal extracellular matrix. We hypothesized that the initiation of pancreatic fibrosis is dependent on the loss of PEDF. Pancreatic PEDF expression was assessed in wild-type mice fed either a control or ethanol diet using an intragastric feeding model. Pancreatitis responses were elicited with either a single episode or a repetitive cerulein-induced (50 μg/kg, 6 hourly i.p. injections) protocol in wild-type and PEDF-null mice. Quantitative real-time PCR and immunoblotting were performed to assess fibrogenic responses. In wild-type animals, PEDF expression increased with pancreatitis and was more pronounced in mice fed ethanol. Compared with wild-type mice, α-smooth muscle actin staining and expression levels of fibrogenic markers (eg, transforming growth factor-β1, platelet-derived growth factor, collagen I, and thrombospondin-1) were higher in PEDF-null mice at baseline. Sirius red staining revealed more fibrosis in PEDF-null versus wild-type pancreas 1 week after pancreatitis. Differences in tissue fibrosis resolved with longer recovery periods. PEDF overexpression suppressed thrombospondin-1 levels in vitro. Ethanol feeding and experimental pancreatitis increased PEDF expression in wild-type mice. PEDF-null mice, however, demonstrated enhanced early fibrotic responses compared with wild-type mice with pancreatitis. These findings indicate that PEDF acts as a compensatory antifibrotic cytokine in pancreatitis.
authors.affiliation: Section of Digestive Diseases, VA Connecticut Healthcare System, New Haven, Connecticut, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Schmitz
authors.forename: Petr
authors.initials: P
authors.lastname: Protiva
authors.forename: Arijeet K
authors.initials: AK
authors.lastname: Gattu
authors.forename: Teruo
authors.initials: T
authors.lastname: Utsumi
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Iwakiri
authors.forename: Antonio G
authors.initials: AG
authors.lastname: Neto
authors.forename: Margo
authors.initials: M
authors.lastname: Quinn
authors.forename: Mona L
authors.initials: ML
authors.lastname: Cornwell
authors.forename: Philip
authors.initials: P
authors.lastname: Fitchev
authors.forename: Aurelia
authors.initials: A
authors.lastname: Lugea
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
authors.forename: Chuhan
authors.initials: C
authors.lastname: Chung
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002108:Ceruletide / Q000633:toxicity; D024042:Collagen Type I / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005136:Eye Proteins / Q000502:physiology*; D005355:Fibrosis; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000172:deficiency / Q000502:physiology*; D010179:Pancreas / Q000473:pathology*; D010195:Pancreatitis / Q000139:chemically induced / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015843:Serpins / Q000172:deficiency / Q000502:physiology*; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D002108:Ceruletide; D024042:Collagen Type I; D005136:Eye Proteins; D009414:Nerve Growth Factors; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D015843:Serpins; D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; D000099174:Pigment Epithelium-Derived Factor