title: Granulocyte colony-stimulating factor reduces fibrosis in a mouse model of chronic pancreatitis.
abstract: BACKGROUND
  Chronic pancreatitis (CP) is a necroinflammatory process resulting in extensive pancreatic fibrosis. Granulocyte colony-stimulating factor (G-CSF), a hematopoietic stem cell mobilizer, has been shown to exert an anti-fibrotic effect partly through the enrichment of bone marrow (BM) cells in fibrotic organ. We aimed to test the effect of G-CSF on fibrosis in a mouse model of CP.
  
  
  METHODS
  CP was induced in C57Bl/6J mice by consecutive cerulein injection (50 µg/kg/day, 2 days a week) for 6 weeks. Mice were then treated with G-CSF (200 µg/kg/day, 5 day a week) or normal saline for 1 week, and sacrificed at week 7 or week 9 after first cerulein injection. Pancreatic histology, pancreatic matrix metallopeptidase 9 (MMP-9), MMP-13 and collagen expression were examined. Pancreatic myofibroblasts were isolated and cultured with G-CSF. Collagen, MMP-9 and MMP-13 expression by myofibroblasts was examined. The BM-mismatched mice model was used to examine the change of BM-derived myofibroblasts and non-myofibroblastic BM cells by G-CSF in the pancreas.
  
  
  RESULTS
  The pancreatic collagen expression were significantly decreased in the G-CSF-treated group sacrificed at week 9. While collagen produced from myofibroblasts was not affected by G-CSF, the increase of MMP13 expression was observed in vitro. There were no effect of G-CSF in the number of myofibroblasts and BM-derived myofibroblasts. However, the number of non-myofibroblastic BM cells and macrophages were significantly increased in the pancreata of cerulein- and G-CSF-treated mice, suggesting a potential anti-fibrotic role of non-myofibroblastic BM cells and macrophages stimulated by G-CSF.
  
  
  CONCLUSIONS
  Our data indicated that G-CSF contributed to the regression of pancreatic fibrosis. The anti-fibrotic effects were possibly through the stimulation of MMP-13 from myofibroblasts, and the enhanced accumulation of non-myofibroblastic BM cells and macrophages in the pancreas.
authors.affiliation: Department of Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; Liver Research Unit, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Wey-Ran
authors.initials: WR
authors.lastname: Lin
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Nephrology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Tzung-Hai
authors.initials: TH
authors.lastname: Yen
authors.affiliation: Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Siew-Na
authors.initials: SN
authors.lastname: Lim
authors.affiliation: Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ming-Der
authors.initials: MD
authors.lastname: Perng
authors.affiliation: Department of Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ming-Yo
authors.initials: MY
authors.lastname: Su
authors.affiliation: Liver Research Unit, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
authors.affiliation: Department of Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Cheng-Tang
authors.initials: CT
authors.lastname: Chiu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D008264:Macrophages / Q000187:drug effects; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D050500:Pancreatitis, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D049452:Green Fluorescent Proteins; D003094:Collagen; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9