title: Protease activation during in vivo pancreatitis is dependent on calcineurin activation.
abstract: The premature activation of digestive proenzymes, specifically proteases, within the pancreatic acinar cell is an early and critical event during acute pancreatitis. Our previous studies demonstrate that this activation requires a distinct pathological rise in cytosolic Ca(2+). Furthermore, we have shown that a target of aberrant Ca(2+) in acinar cells is the Ca(2+)/calmodulin-dependent phosphatase calcineurin (PP2B). In this study, we hypothesized that PP2B mediates in vivo protease activation and pancreatitis severity. To test this, pancreatitis was induced in mice over 8 h by administering hourly intraperitoneal injections of the cholecystokinin analog caerulein (50 microg/kg). Treatment with the PP2B inhibitor FK506 at 1 and 8 h after pancreatitis induction reduced trypsin activities by greater than 50% (P < 0.005). Serum amylase and IL-6 was reduced by 86 and 84% relative to baseline (P < 0.0005) at 8 h, respectively. Histological severity of pancreatitis, graded on the basis of pancreatic edema, acinar cell vacuolization, inflammation, and apoptosis, was reduced early in the course of pancreatitis. Myeloperoxidase activity from both pancreas and lung was reduced by 93 and 83% relative to baseline, respectively (P < 0.05). These data suggest that PP2B is an important target of the aberrant acinar cell Ca(2+) rise associated with pathological protease activation and pancreatitis.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ahsan U
authors.initials: AU
authors.lastname: Shah
authors.forename: Amna
authors.initials: A
authors.lastname: Sarwar
authors.forename: Abrahim I
authors.initials: AI
authors.lastname: Orabi
authors.forename: Samir
authors.initials: S
authors.lastname: Gautam
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Grant
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Park
authors.forename: Adnan U
authors.initials: AU
authors.lastname: Shah
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Mistry
authors.forename: Dhanpat
authors.initials: D
authors.lastname: Jain
authors.forename: Sohail Z
authors.initials: SZ
authors.lastname: Husain
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002108:Ceruletide / Q000494:pharmacology; D004789:Enzyme Activation; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055292:Pancreatic alpha-Amylases / Q000097:blood; D010195:Pancreatitis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D010447:Peptide Hydrolases / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D014357:Trypsin / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D018840:HSP70 Heat-Shock Proteins; D015850:Interleukin-6; D002108:Ceruletide; D009195:Peroxidase; D019703:Calcineurin; D055292:Pancreatic alpha-Amylases; D010447:Peptide Hydrolases; D014357:Trypsin; D016559:Tacrolimus