title: Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis.
abstract: Pancreatic acinar cells express proteinase-activated receptor-2 (PAR2) that is activated by trypsin-like serine proteases and has been shown to exert model-specific effects on the severity of experimental pancreatitis, i.e., PAR2(-/-) mice are protected from experimental acute biliary pancreatitis but develop more severe secretagogue-induced pancreatitis. P2pal-18S is a novel pepducin lipopeptide that targets and inhibits PAR2. In studies monitoring PAR2-stimulated intracellular Ca(2+) concentration changes, we show that P2pal-18S is a full PAR2 inhibitor in acinar cells. Our in vivo studies show that P2pal-18S significantly reduces the severity of experimental biliary pancreatitis induced by retrograde intraductal bile acid infusion, which mimics injury induced by endoscopic retrograde cholangiopancreatography (ERCP). This reduction in pancreatitis severity is observed when the pepducin is given before or 2 h after bile acid infusion but not when it is given 5 h after bile acid infusion. Conversely, P2pal-18S increases the severity of secretagogue-induced pancreatitis. In vitro studies indicate that P2pal-18S protects acinar cells against bile acid-induced injury/death, but it does not alter bile acid-induced intracellular zymogen activation. These studies are the first to report the effects of an effective PAR2 pharmacological inhibitor on pancreatic acinar cells and on the severity of experimental pancreatitis. They raise the possibility that a pepducin such as P2pal-18S might prove useful in the clinical management of patients at risk for developing severe biliary pancreatitis such as occurs following ERCP.
authors.affiliation: Department of Surgery, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Michael
authors.forename: A
authors.initials: A
authors.lastname: Kuliopulos
authors.forename: L
authors.initials: L
authors.lastname: Covic
authors.forename: M L
authors.initials: ML
authors.lastname: Steer
authors.forename: G
authors.initials: G
authors.lastname: Perides
mesh_terms: D061354:Acinar Cells / Q000187:drug effects; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001660:Biliary Tract Diseases / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002108:Ceruletide / Q000494:pharmacology; D002760:Cholangiopancreatography, Endoscopic Retrograde; D002919:Chymotrypsinogen / Q000378:metabolism; D004396:Coloring Agents; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism; D042882:Gallstones / Q000517:prevention & control; D007202:Indicators and Reagents; D055666:Lipopeptides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010195:Pancreatitis / Q000517:prevention & control*; D011419:Propidium; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors*; D014362:Trypsinogen / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D004396:Coloring Agents; D004792:Enzyme Precursors; D007202:Indicators and Reagents; D055666:Lipopeptides; C580591:P2pal-18S pepducin; D044464:Receptor, PAR-2; D011419:Propidium; D002108:Ceruletide; D014362:Trypsinogen; D002919:Chymotrypsinogen; D002118:Calcium