Background. With the ex vivo perfused canine pancreas preparation, the infusion of acetaldehyde, the primary metabolite of ethanol oxidation, plus a short period of ischemia to convert xanthine dehydrogenase to xanthine oxidase, results in the physiologic injury response of acute pancreatitis (edema, weight gain, hyperamylasemia). The free radical scavengers superoxide dismutase and catalase and a xanthine oxidase inhibitor, allopurinol, ameliorate this injury response, suggesting that toxic oxygen metabolites generated by xanthine oxidase play an intermediary role. Methods. The isolated ex vivo canine pancreas preparation was perfused for 4 hours, and weight gain of the preparation and amylase activity in the perfusate were monitored. Changes in pancreatic acinar cell architecture were characterized by light and electron microscopy, and intracellular phosphate metabolism was followed by magnetic resonance spectroscopy in control preparations and in glands simulating alcoholic pancreatitis. Results. Control preparations and preparations with a 1-hour period of ischemia before perfusion gained little weight (7±3 gm and 8±1 gm), amylase activity in the perfusate remained normal (933±513 units/dl and 1537±553 units/dl), and no changes in architecture were observed. Weight gain (5±6 gm) and amylase activity (1188±173 units/dl) were also normal in the preparations receiving acetaldehyde without preceding ischemia, but mild vascular and islet cell injury were observed on electron microscopy. One hour of ischemia followed by acetaldehyde infusion resulted in edema, increased weight gain (21±12 gm [p<0.05]), and amylase activity (2487±1484 units/dl [p<0.05]). Microscopy showed mild acinar cell damage and greater injury to the capillaries and the islets. The capillary and islet cell changes were reduced by superoxide dismutase and catalase. Intracellular adenosine triphosphate levels remained at baseline levels in the control preparations. Adenosine triphosphate decreased during ischemia but quickly recovered during perfusion without a significant difference whether acetaldehyde was infused after ischemia. An iron chelator desferoxamine ameliorated the injury response in the preparations simulating acute pancreatitis (weight gain, 13±6 gm [p=0.09] and amylase activity, 1198±471 units/dl [p=0.08]), but a cholecystokinin receptor antagonist L364,718 did not have an effect. A sulfhydryl group protector, dithiothreitol, decreased weight gain (10±7 gm [p=0.06]), and amylase activity was not significantly increased over that of the control group (1582±641 units/dl), but a serine protease inhibitor phenylmethylsulphonylfluoride was ineffective. Conclusions. In this model simulating acute alcoholic pancreatitis, both the early physiologic injury response and the early morphologic changes are mediated at least in part by free radicals, which are generated by xanthine oxidase converted reversibly from xanthine dehydrogenase. In addition to the superoxide radical, the hydroxyl radical may also be an important early intermediate step, but the cholecystokinin receptor is not.
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