title: Suppression of transforming growth factor beta signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations.
abstract: BACKGROUND
  Transforming growth factors betas (TGF-betas) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF-betas modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild-type (FVB-/-) and transgenic mice that are heterozygous (FVB+/-) for expression of a dominant negative type II TGF-beta receptor.
  
  
  METHODS
  After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed.
  
  
  RESULTS
  The normal mouse pancreas was devoid of inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild-type mice resulted in 6- and 36-fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/- mice exhibited minimal alterations in response to caerulein with attenuated neutrophil-macrophage infiltrates. Moreover, acini from FVB+/- mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased.
  
  
  CONCLUSIONS
  Our findings indicate that a functional TGF-beta signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.
authors.affiliation: Department of Medicine and Pharmacology & Toxicology, Dartmouth Medical School, Hanover, New Hampshire, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wildi
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.forename: Arthur
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Erwin P
authors.initials: EP
authors.lastname: Böttinger
authors.forename: Lalage
authors.initials: L
authors.lastname: Wakefield
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
mesh_terms: D000208:Acute Disease; D000681:Amylases / Q000097:blood / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D002108:Ceruletide; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D008024:Ligands; D008049:Lipase / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000097:blood; D010182:Pancreatic Diseases / Q000139:chemically induced / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D008024:Ligands; D009842:Oligopeptides; D011949:Receptors, Cholecystokinin; D016212:Transforming Growth Factor beta; C080396:trypsinogen activation peptide; D002108:Ceruletide; D008049:Lipase; D000681:Amylases