title: Acinar cell-specific knockout of the PTHrP gene decreases the proinflammatory and profibrotic responses in pancreatitis.
abstract: Pancreatitis is a necroinflammatory disease with acute and chronic manifestations. Accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic pancreatitis (CP). Pancreatic parathyroid hormone-related protein (PTHrP) levels are elevated in a mouse model of cerulein-induced AP. Here, we show elevated PTHrP levels in mouse models of pancreatitis induced by chronic cerulein administration and pancreatic duct ligation. Because acinar cells play a major role in the pathophysiology of pancreatitis, mice with acinar cell-specific targeted disruption of the Pthrp gene (PTHrP(Δacinar)) were generated to assess the role of acinar cell-secreted PTHrP in pancreatitis. These mice were generated using Cre-LoxP technology and the acinar cell-specific elastase promoter. PTHrP(Δacinar) exerted protective effects in cerulein and pancreatic duct ligation models, evident as decreased edema, histological damage, amylase secretion, pancreatic stellate cell (PSC) activation, and extracellular matrix deposition. Treating acinar cells in vitro with cerulein increased IL-6 expression and NF-κB activity; these effects were attenuated in PTHrP(Δacinar) cells, as were the cerulein- and carbachol-induced elevations in amylase secretion. The cerulein-induced upregulation of procollagen I expression was lost in PSCs from PTHrP(Δacinar) mice. PTHrP immunostaining was elevated in human CP sections. The cerulein-induced upregulation of IL-6 and ICAM-1 (human acinar cells) and procollagen I (human PSCs) was suppressed by pretreatment with the PTH1R antagonist, PTHrP (7-34). These findings establish PTHrP as a novel mediator of inflammation and fibrosis associated with CP. Acinar cell-secreted PTHrP modulates acinar cell function via its effects on proinflammatory cytokine release and functions via a paracrine pathway to activate PSCs.
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas;
authors.forename: Vandanajay
authors.initials: V
authors.lastname: Bhatia
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas;
authors.forename: Cristiana
authors.initials: C
authors.lastname: Rastellini
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas;
authors.forename: Song
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas; and.
authors.forename: Judith F
authors.initials: JF
authors.lastname: Aronson
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas;
authors.forename: George H
authors.initials: GH
authors.lastname: Greeley
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas; Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, Texas mfalzon@utmb.edu.
authors.forename: Miriam
authors.initials: M
authors.lastname: Falzon
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism*; D000681:Amylases / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D002108:Ceruletide / Q000633:toxicity; D005355:Fibrosis / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010183:Pancreatic Ducts / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D011347:Procollagen / Q000235:genetics / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D044162:Parathyroid Hormone-Related Protein; D011347:Procollagen; D018799:Intercellular Adhesion Molecule-1; D002108:Ceruletide; D002217:Carbachol; D000681:Amylases
keywords: acinar cells; pancreatitis; parathyroid hormone-related protein; stellate cells