title: Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice.
abstract: Chronic pancreatitis (CP) is a devastating disease with no treatments. Experimental models have been developed to reproduce the parenchyma and inflammatory responses typical of human CP. For the present study, one objective was to assess and compare the effects of pancreatic duct ligation (PDL) to those of repetitive cerulein (Cer)-induced CP in mice on pancreatic production of bone morphogenetic protein-2 (BMP2), apelin, and parathyroid hormone-related protein (PTHrP). A second objective was to determine the extent of cross talk among pancreatic BMP2, apelin, and PTHrP signaling systems. We focused on BMP2, apelin, and PTHrP since these factors regulate the inflammation-fibrosis cascade during pancreatitis. Findings showed that PDL- and Cer-induced CP resulted in significant elevations in expression and peptide/protein levels of pancreatic BMP2, apelin, and PTHrP. In vivo mouse and in vitro pancreatic cell culture experiments demonstrated that BMP2 stimulated pancreatic apelin expression whereas apelin expression was inhibited by PTHrP exposure. Apelin or BMP2 exposure inhibited PTHrP expression, and PTHrP stimulated upregulation of gremlin, an endogenous inhibitor of BMP2 activity. Transforming growth factor-β (TGF-β) stimulated PTHrP expression. Together, findings demonstrated that PDL- and Cer-induced CP resulted in increased production of the pancreatic BMP2, apelin, and PTHrP signaling systems and that significant cross talk occurred among pancreatic BMP2, apelin, and PTHrP. These results together with previous findings imply that these factors interact via a pancreatic network to regulate the inflammation-fibrosis cascade during CP. More importantly, this network communicated with TGF-β, a key effector of pancreatic pathophysiology. This novel network may be amenable to pharmacologic manipulations during CP in humans.
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas; and.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Rastellini
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas; and.
authors.forename: Song
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas; and.
authors.forename: Vandanajay
authors.initials: V
authors.lastname: Bhatia
authors.affiliation: Department of Surgery, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Surgery, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Ka
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Surgery, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Xuxia
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Surgery, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Tien C
authors.initials: TC
authors.lastname: Ko
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas; and ghgjr6864@utmb.edu.
authors.forename: George H
authors.initials: GH
authors.lastname: Greeley
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas; and.
authors.forename: Miriam
authors.initials: M
authors.lastname: Falzon
mesh_terms: D054392:Adipokines / Q000378:metabolism*; D000818:Animals; D000073861:Apelin; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D018929:Cell Culture Techniques; D002108:Ceruletide / Q000494:pharmacology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008026:Ligation; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D010183:Pancreatic Ducts / Q000601:surgery*; D050500:Pancreatitis, Chronic / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D054392:Adipokines; D000073861:Apelin; C402826:Apln protein, mouse; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D036341:Intercellular Signaling Peptides and Proteins; D044162:Parathyroid Hormone-Related Protein; D002108:Ceruletide
keywords: cross talk; fibrosis; inflammation; interaction; network; signaling