title: Enhanced expression of TGF-betas and their receptors in human acute pancreatitis.
abstract: OBJECTIVE
  To determine which mechanisms are involved in pancreatic remodeling, repair, and fibrosis after acute necrotizing pancreatitis (NP) in humans.
  
  
  BACKGROUND
  Transforming growth factor betas (TGF-betas) are multifunctional polypeptides that have been implicated in the regulation and formation of extracellular matrix and fibrosis. They exert their functions by binding to specific receptors. In this study, we analyze the expression of TGF-beta1, TGF-beta2, and TGF-beta3 and their receptors type I (Tbeta-RI [ALK5]), type II (Tbeta-RII), and type III (Tbeta-RIII) in NP.
  
  
  METHODS
  Pancreatic tissue samples were obtained from 6 female and 8 male patients with a median age of 65 years (range, 37 to 77 years) undergoing surgery for NP. The median Ranson score of the patients was 6 (range, 2 to 9). The operation was performed a median 5.5 days (range, 4 to 17 days) after the onset of acute pancreatitis. Pancreatic tissue obtained from 12 previously healthy organ donors (6 male, 6 female; median age of 43 years) served as controls.
  
  
  METHODS
  The expression of TGF-beta1, TGF-beta2, TGF-beta3, Tbeta-RI (ALK5), Tbeta-RII, Tbeta-RIII, and collagen type I mRNA was analyzed by Northern blot analysis. In addition, immunohistochemical analysis using polyclonal antibodies was performed to detect TGF-beta1, TGF-beta2, TGF-beta3, Tbeta-RI (ALK5), and Tbeta-RII.
  
  
  RESULTS
  Northern blot analysis showed an increase in TGF-betas and their receptors in NP tissue samples compared with samples from normal controls. The increase was 3.5-fold for TGF-beta1 (p < 0.05), 2.7-fold for TGF-beta2 (p < 0.05), 3.5-fold for TGF-beta3 (p < 0.05), 10-fold for Tbeta-RI (ALK5) (p < 0.05), 5.7-fold for Tbeta-RII (p < 0.05), and 1.4-fold for Tbeta-RIII (not significant). Collagen type I mRNA was also markedly increased in NP samples and correlated with the level of TGF-betas. Immunohistochemical analysis demonstrated intense TGF-beta1, TGF-beta2, TGF-beta3, Tbeta-RI (ALK5), and Tbeta-RII immunoreactivity in the remaining acinar and ductal cells in most NP samples; in the normal control pancreas, there was weak to moderate immunoreactivity for these factors only in some acinar cells and a few ductal cells.
  
  
  CONCLUSIONS
  The marked increase in expression of TGF-betas and their signaling receptors Tbeta-RI (ALK5) and Tbeta-RII suggests a role for TGF-betas in the repair process after the onset of NP in humans and raises the possibility that TGF-betas might be involved in tissue remodeling and the fibrotic reaction that occurs in the pancreas after necrosis.
authors.affiliation: Department of Visceral and Transplantation Surgery, University of Bern, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Friess
authors.forename: Z
authors.initials: Z
authors.lastname: Lu
authors.forename: E
authors.initials: E
authors.lastname: Riesle
authors.forename: W
authors.initials: W
authors.lastname: Uhl
authors.forename: A M
authors.initials: AM
authors.lastname: Bründler
authors.forename: L
authors.initials: L
authors.lastname: Horvath
authors.forename: L I
authors.initials: LI
authors.lastname: Gold
authors.forename: M
authors.initials: M
authors.lastname: Korc
authors.forename: M W
authors.initials: MW
authors.lastname: Büchler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015152:Blotting, Northern; D016022:Case-Control Studies; D005260:Female; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D010180:Pancreatectomy; D019283:Pancreatitis, Acute Necrotizing / Q000276:immunology* / Q000473:pathology* / Q000601:surgery; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis*; D012038:Regeneration; D012720:Severity of Illness Index
chemical_list: C505697:LTBR protein, human; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D018124:Receptors, Tumor Necrosis Factor