PLATELET-ACTIVATING-FACTOR - A MEDIATOR OF PANCREATIC INFLAMMATION DURING CERULEIN HYPERSTIMULATION

Hyperstimulation of the exocrine pancreas with cerulein causes acute p ancreatitis, characterized by intensive interstitial edema, acinar vac uolization, leukocytic infiltration, and hyperamylasemia Whereas the p athogenesis of cerulein-induced pancreatitis is not well-defined, a lo cal inflammatory response may contribute to the full expression of acu te pancreatitis. Platelet-activating factor (PAF) seems to be an impor tant mediator of the inflammatory response. The present evidence inclu des: 1) pancreatic PAF levels increased in rats in which cerulein-indu ced pancreatitis was initiated, concomitant with an increase in calciu m concentrations in the pancreatic tissue, 2) treatment of rats expose d to cerulein with WEB2170, a PAF receptor antagonist, was shown to re duce inflammatory injury, as demonstrated by decreases in pancreatic w eight, Evan's blue extravasation, and myeloperoxidase activity and an improvement in pancreatic histology. In an idealized in vitro experime nt mimicking cerulein-induced acute pancreatitis, in which pancreatic acini were employed, cerulein induced amylase release, an increase in [Ca2+]i, and an increase in PAF synthesis. Whereas amylase release was induced by low concentrations of cerulein (10(-11) mol/L), relatively high concentrations of cerulein (10(-9) mol/L) were required for the observed increases in PAF synthesis and the [Ca2+]i, indicating that t hese two responses may not occur under physiological conditions. The p resent study suggests that the pancreatic accumulation of PAF coupled with Ca2+ overload are important biochemical components of the pathoph ysiology of cerulein-induced acute pancreatitis. In fact, PAF producti on may serve as a primary mediator of inflammation observed during pan creatic hyperstimulation. This is an important observation that will a llow a more detailed characterization of the molecular basis of cerule in-induced acute pancreatitis.