Protease-activated receptor-2 protects against pancreatitis by stimulating exocrine secretion.
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.


OBJECTIVE
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.
Singh
Vijay P
VP
Department of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA.
Bhagat
Lakshmi
L
Navina
Sarah
S
Sharif
Rifat
R
Dawra
Rajinder K
RK
Saluja
Ashok K
AK
D000208:Acute Disease; D000681:Amylases / Q000378:metabolism; D000818:Animals; D001120:Arginine; D002108:Ceruletide; D004195:Disease Models, Animal; D004789:Enzyme Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046790:Pancreas, Exocrine / Q000378:metabolism*; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D044464:Receptor, PAR-2 / Q000235:genetics / Q000502:physiology*; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000096:biosynthesis; D014357:Trypsin / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D012333:RNA, Messenger; D044464:Receptor, PAR-2; D014157:Transcription Factors; D002108:Ceruletide; D001120:Arginine; D000681:Amylases; D014357:Trypsin