activated polyamine catabolism in acute pancreatitis: alpha-methylated polyamine analogues prevent trypsinogen activation and pancreatitis-associated mortality.
Polyamines are essential for normal cellular growth and function. Activation of polyamine catabolism in transgenic rats overexpressing spermidine/spermine N(1)-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 N(1)-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.
Hyvönen
Mervi T
MT
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland.
Herzig
Karl-Heinz
KH
Sinervirta
Riitta
R
Albrecht
Elke
E
Nordback
Isto
I
Sand
Juhani
J
Keinänen
Tuomo A
TA
Vepsäläinen
Jouko
J
Grigorenko
Nikolay
N
Khomutov
Alex R
AR
Krüger
Burkhard
B
Jänne
Juhani
J
Alhonen
Leena
L
D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D030781:Organisms, Genetically Modified; D019283:Pancreatitis, Acute Necrotizing / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014362:Trypsinogen / Q000378:metabolism*
D015317:Biogenic Polyamines; D014362:Trypsinogen