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(American Journal of Pathology. 2006;168:115-122.)
© 2006 American Society for Investigative Pathology

Activated Polyamine Catabolism in Acute Pancreatitis

{alpha}-Methylated Polyamine Analogues Prevent Trypsinogen Activation and Pancreatitis-Associated Mortality

Mervi T. Hyvönen*, Karl-Heinz Herzig*, Riitta Sinervirta*, Elke Albrecht{dagger}, Isto Nordback{ddagger}, Juhani Sand{ddagger}, Tuomo A. Keinänen*, Jouko Vepsäläinen§, Nikolay Grigorenko, Alex R. Khomutov, Burkhard Krüger{dagger}, Juhani Jänne* and Leena Alhonen*

From the Department of Biotechnology and Molecular Medicine,* A.I. Virtanen Institute for Molecular Sciences, and the Department of Chemistry,§ University of Kuopio, Kuopio, Finland; the Department of Gastroenterology and Alimentary Tract Surgery,{ddagger} Tampere University Hospital, Tampere, Finland; the Division of Medical Biology,{dagger} Institute of Pathology, University of Rostock, Rostock, Germany; and Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia

Polyamines are essential for normal cellular growth and function. Activation of polyamine catabolism in transgenic rats overexpressing spermidine/spermine N1-acetyltransferase, the key enzyme in polyamine catabolism, results in severe acute pancreatitis. Here, we investigated the role of polyamine catabolism in pancreatitis and studied the effect of polyamine analogues on the outcome of the disease. Polyamine depletion was associated with arginine- and cerulein-induced pancreatitis as well as with human acute necrotizing and chronic secondary pancreatitis. Substitution of depleted polyamine pools with methylspermidine partially prevented arginine-induced necrotizing pancreatitis whereas cerulein-induced edematous pancreatitis remained unaffected. Transgenic rats receiving methylated polyamine analogues after the induction of pancreatitis showed less pancreatic damage than the untreated rats. Most importantly, polyamine analogues dramatically rescued the animals from pancreatitis-associated mortality. Induction of spermidine/spermine N1-acetyltransferase in acinar cells isolated from transgenic rats resulted in increased trypsinogen activation. Pretreatment of acini with bismethylspermine prevented trypsinogen activation, indicating that premature proteolytic activation is one of the effects triggered by polyamine depletion. Our data suggest that activation of polyamine catabolism is a general pathway in the pathogenesis of acute pancreatitis and that experimental disease can be ameliorated with stable polyamine analogues.




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