Role of phospholipase A2 in pancreatic acinar cell damage and possibilities of inhibition: studies with isolated rat pancreatic acini.
Phospholipase A2 (PLA2) has been postulated to play an important role in the pathogenesis of acute pancreatitis. To study the mechanism through which PLA2 may cause cellular damage, we used an in vitro model of isolated rat pancreatic acini prepared by collagenase digestion. Newly synthesized proteins were labeled by [35S]methionine. Cellular destruction was measured by the degree of release of radiolabeled proteins. Incubation of pancreatic acini with PLA2 alone caused only minor damage when very high concentrations of this enzyme were used. However, when acini were incubated with PLA2 in combination with its substrate, lecithin, cells were destroyed in a time- and concentration-dependent manner. Incubating cells with pancreatic homogenates and lecithin caused damage only when there had been prior activation of homogenates with either trypsin or enterokinase. The damage could be simulated by incubating acini with pure lysolecithin. Alcohol and cerulein did not further increase the destruction caused by PLA2 and lecithin. When acini were incubated with supernatants from another set of acini to which oleic acid had been added, a similar degree of damage resulted as compared with acini incubated with oleic acid alone. However, adding PLA2 to supernatants from acini preincubated with fatty acids significantly increased the degree of cellular necrosis. The destruction by PLA2 and lecithin was inhibited by albumin but could not be inhibited by gabexate mesilate, nafamostat mesilate, or cytidine diphosphocholine. We conclude that PLA2 could play a role in pancreatic acinar cell damage, especially in the spread of cellular necrosis within the organ, provided that its substrate, lecithin, is present.(ABSTRACT TRUNCATED AT 250 WORDS)
Kimura
W
W
Medizinische Poliklinik, University of Würzburg, Germany.
Secknus
R
R
Fischbach
W
W
Mössner
J
J
D000208:Acute Disease; D000418:Albumins / Q000494:pharmacology; D000818:Animals; D002108:Ceruletide / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D019301:Oleic Acid; D009829:Oleic Acids / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010195:Pancreatitis / Q000209:etiology; D010713:Phosphatidylcholines / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D054467:Phospholipases A2; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000418:Albumins; D009829:Oleic Acids; D010713:Phosphatidylcholines; D011506:Proteins; D019301:Oleic Acid; D000431:Ethanol; D002108:Ceruletide; D002766:Cholecystokinin; D010741:Phospholipases A; D054467:Phospholipases A2