METALLOTHIONEIN PROTECTS AGAINST CERULEIN-INDUCED ACUTE-PANCREATITIS - ANALYSIS USING TRANSGENIC MICE

Oxidative stress has been proposed to play a role in the early events of acute pancreatitis, and metallothionein (MT) can provide protection against oxidative stress. Using transgenic mice, we characterized the effects of depletion of MT-I and -II, or overexpression of MT-I, on p ancreatic responses during cerulein-induced acute pancreatitis. In MT- I/-II knockout mice, repeated injections of cerulein caused (a) higher serum amylase levels at 3 and 7 h after the initiation of acute pancr eatitis; (b) earlier and stronger upregulation of oxidative stress-res ponsive genes, including heme oxygenase (HO)-1 and c-fos; and (c) exac erbated tissue damage (edema and polymorphonuclear neutrophil infiltra tion) compared with nontransgenic 129/SvCPJ mice. Total pancreatic glu tathione (GSH + GSSG) content was similar between the knockout and non transgenic 129/SvCPJ mice. Interestingly, during acute pancreatitis, C D-I mice pretreated with L-buthionine-[S,R]sulfoximine (BSO), which dr amatically depleted pancreatic GSH, also had more severe pancreatitis, based on the same three criteria listed above, relative to untreated controls. No effects were observed with BSO treatment alone. Finally, during cerulein-induced acute pancreatitis, MT-I overexpressing transg enic mice (>20-fold increase in pancreatic MT-I content) had lower ser um alpha-amylase levels between 7 and 24 h and delayed upregulation of HO-1 mRNA levels, but no difference in c-fos mRNA induction relative to the appropriate strain of nontransgenic mice. Diminished tissue dam age (particularly cellular necrosis) was noted in these MT-I overexpre ssing transgenic mice. Total pancreatic GSH content was similar in the se transgenic and nontransgenic mice during cerulein-induced acute pan creatitis. These studies suggest that pancreatic MT can function as an intracellular antioxidant as does GSH and that these intracellular an tioxidants play a protective role during cerulein-induced acute pancre atitis.