title: Serine proteases mediate inflammatory pain in acute pancreatitis.
abstract: Acute pancreatitis is a life-threatening inflammatory disease characterized by abdominal pain of unknown etiology. Trypsin, a key mediator of pancreatitis, causes inflammation and pain by activating protease-activated receptor 2 (PAR(2)), but the isoforms of trypsin that cause pancreatitis and pancreatic pain are unknown. We hypothesized that human trypsin IV and rat P23, which activate PAR(2) and are resistant to pancreatic trypsin inhibitors, contribute to pancreatic inflammation and pain. Injections of a subinflammatory dose of exogenous trypsin increased c-Fos immunoreactivity, indicative of spinal nociceptive activation, but did not cause inflammation, as assessed by measuring serum amylase and myeloperoxidase activity and by histology. The same dose of trypsin IV and P23 increased some inflammatory end points and caused a more robust effect on nociception, which was blocked by melagatran, a trypsin inhibitor that also inhibits polypeptide-resistant trypsin isoforms. To determine the contribution of endogenous activation of trypsin and its minor isoforms, recombinant enterokinase (ENK), which activates trypsins in the duodenum, was administered into the pancreas. Intraductal ENK caused nociception and inflammation that were diminished by polypeptide inhibitors, including soybean trypsin inhibitor and a specific trypsin inhibitor (type I-P), and by melagatran. Finally, the secretagogue cerulein induced pancreatic nociceptive activation and nocifensive behavior that were reversed by melagatran. Thus trypsin and its minor isoforms mediate pancreatic pain and inflammation. In particular, the inhibitor-resistant isoforms trypsin IV and P23 may be important in mediating prolonged pancreatic inflammatory pain in pancreatitis. Our results suggest that inhibitors of these isoforms could be novel therapies for pancreatitis pain.
authors: Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors: Eugene P
authors: EP
authors: Ceppa
authors: Victoria
authors: V
authors: Lyo
authors: Eileen F
authors: EF
authors: Grady
authors: Wolfgang
authors: W
authors: Knecht
authors: Sarah
authors: S
authors: Grahn
authors: Anders
authors: A
authors: Peterson
authors: Nigel W
authors: NW
authors: Bunnett
authors: Kimberly S
authors: KS
authors: Kirkwood
authors: Fiore
authors: F
authors: Cattaruzza
mesh_terms: D015746:Abdominal Pain / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002108:Ceruletide; D004195:Disease Models, Animal; D004765:Enteropeptidase / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D008297:Male; D010147:Pain Measurement; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D009195:Peroxidase / Q000097:blood; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044464:Receptor, PAR-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D030262:Soybean Proteins / Q000494:pharmacology; D013116:Spinal Cord / Q000201:enzymology; D014357:Trypsin / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000494:pharmacology
chemical_list: D000700:Analgesics; D001384:Azetidines; D001596:Benzylamines; D016760:Proto-Oncogene Proteins c-fos; D044464:Receptor, PAR-2; D011994:Recombinant Proteins; D030262:Soybean Proteins; D014361:Trypsin Inhibitors; C109573:melagatran; D002108:Ceruletide; D009195:Peroxidase; D000681:Amylases; C040749:PRSS3 protein, human; D014357:Trypsin; D004765:Enteropeptidase