title: Apoptosis and proliferation of acinar and islet cells in chronic pancreatitis: evidence for differential cell loss mediating preservation of islet function.
abstract: BACKGROUND
  Chronic pancreatitis is characterised clinically by early exocrine insufficiency, with diabetes mellitus occurring as a late phenomenon. This is mirrored pathologically by extensive acinar cell destruction and islet preservation. The mechanisms underlying this differential rate of cellular destruction are unknown.
  
  
  OBJECTIVE
  To test the hypothesis that acinar loss and islet preservation in chronic pancreatitis occurs due to differential epithelial kinetics and investigate the role of inflammatory cells and cell cycle associated molecules.
  
  
  METHODS
  Archival tissue from six chronic pancreatitis cases was compared with six normal controls using TUNEL and immunohistochemistry for CD3, CD20, CD68, MIB-1, Bcl-2, Bax, Fas, Fas ligand, retinoblastoma protein (Rb), and tissue inhibitor of metalloproteinases 1 (TIMP-1) and 2 (TIMP-2).
  
  
  RESULTS
  The acinar cell apoptotic index (AI) and proliferation index were higher in chronic pancreatitis than controls. T lymphocytes diffusely infiltrated fibrous bands and acini but rarely islets. Acinar Bcl-2 expression exceeded islet expression in chronic pancreatitis and controls while Bax was strongly expressed by a subset of islet cells and weakly by centroacinar cells. Islet Fas and Fas ligand expression exceeded acinar expression in chronic pancreatitis and controls. Acinar Rb expression was higher in chronic pancreatitis than in controls. Islets in chronic pancreatitis and controls showed intense TIMP-1 and TIMP-2 expression.
  
  
  CONCLUSIONS
  Apoptosis plays a significant role in acinar loss in chronic pancreatitis. Acinar Bcl-2 and islet Bax expression indicates complex AI control. Increased acinar Rb expression in chronic pancreatitis may differentially promote acinar loss. Fas ligand expression may be restricted to islet cell membranes through TIMP-1 expression and inhibit islet damage by promoting apoptosis of cytotoxic T lymphocytes.
authors.affiliation: The Pancreatic and Liver Fibrosis Research Groups, Division of Infection, University of Southampton, Southampton General Hospital, UK. adrian.bateman@suht.swest.nhs.uk
authors.forename: A C
authors.initials: AC
authors.lastname: Bateman
authors.forename: S M
authors.initials: SM
authors.lastname: Turner
authors.forename: K S A
authors.initials: KS
authors.lastname: Thomas
authors.forename: P R
authors.initials: PR
authors.lastname: McCrudden
authors.forename: D R
authors.initials: DR
authors.lastname: Fine
authors.forename: P A
authors.initials: PA
authors.lastname: Johnson
authors.forename: C D
authors.initials: CD
authors.lastname: Johnson
authors.forename: J P
authors.initials: JP
authors.lastname: Iredale
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002455:Cell Division; D002908:Chronic Disease; D004847:Epithelial Cells / Q000473:pathology; D053222:Fas Ligand Protein; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D010195:Pancreatitis / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019715:Tissue Inhibitor of Metalloproteinase-1; D051028:bcl-2-Associated X Protein; D019716:Tissue Inhibitor of Metalloproteinase-2