Article Text

PDF
Protease-activated receptor-2 protects against pancreatitis by stimulating exocrine secretion
  1. Vijay P Singh1,
  2. Lakshmi Bhagat2,
  3. Sarah Navina3,
  4. Rifat Sharif4,
  5. Rajinder K Dawra4,
  6. Ashok K Saluja4
  1. 1Department of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
  2. 2Idera Pharmaceuticals, Cambridge, Massachusetts, USA
  3. 3Department of Pathology, University of Minnesota, Minneapolis, Minnesota, USA
  4. 4Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
  1. Correspondence to:
    Dr A K Saluja
    Department of Surgery, MMC 195, 420 Delaware Street SE, Minneapolis, MN 55455, USA; asaluja{at}umn.edu

Abstract

Background: Protease-activated receptor-2 (PAR-2) is present in the pancreas, where it has been shown to play a protective role during pancreatitis. However, the mechanism by which it protects against pancreatitis still remains to be elucidated. Acute pancreatitis is associated with premature zymogen activation and a blockage in digestive enzyme secretion.

Aim: To examine the effects of PAR-2 activation on the severity of pancreatitis, and to determine whether its protective effects are mediated by affecting either premature activation or secretory blockage, or both.

Results: The results confirmed that PAR-2 −/− mice have more severe pancreatitis than wild-type mice. Interestingly, intrapancreatic trypsin levels in the PAR-2 knockouts remained high after 6 h of pancreatitis, whereas they reverted to normal in the wild types. During pancreatitis, PAR-2 mRNA levels were upregulated in wild-type mice in response to supramaximal caerulein administration. Further, after a single injection of supramaximal caerulein, PAR-2 mRNA levels were also elevated, reaching a peak at 3 h. Stimulating PAR-2 with trypsin or the PAR-2-activating peptide, serine-leucine-isoleucine-glycine-arginine-leucine (SLIGRL), induced significantly more secretion from the acini of these caerulein-sensitised mice compared with the controls. PAR-2 activation also reversed the inhibition of secretion observed in both the caerulein and arginine models.

Conclusions: Trypsin released during the early stages of pancreatitis activates PAR-2 receptors on the acinar cells and stimulates secretion from these cells. Thus, PAR-2 activation may decrease pancreatic injury and limit the severity of pancreatitis by allowing extracellular trypsin to act as a secretagogue.

  • AP-1, activator-protein 1
  • CER, caerulein
  • EMSA, electrophoretic mobility-shift assay
  • LRGILS, leucine-arginine-glycine-isoleucine-leucine-serine
  • MOPS, 3-(N-morpholino)-propane sulphonic acid
  • NFκB, nuclear factor kappa B
  • PAR-2, protease-activated receptor 2
  • SLIGRL, serine-leucine-isoleucine-glycine-arginine-leucine
  • TBE, tris-borate buffer

Statistics from Altmetric.com

Footnotes

  • Published Online First 17 November 2006

  • Competing interests: None declared.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Linked Articles