PROTECTIVE EFFECT OF 4-HYDROXY-TEMPO, A LOW-MOLECULAR-WEIGHT SUPEROXIDE-DISMUTASE MIMIC, ON FREE-RADICAL TOXICITY IN EXPERIMENTAL PANCREATITIS

Rats develop acute pancreatitis when infused iv for 3 h with cerulein (10 mu g/kg/h). Autopsies of the pancreas seen by light microscope sha w interstitial edema, acinar cells vacuolization, and leukocyte margin ation in pancreatic capillaries; under electron microscope, severe dam age concerning mitochondrial and zymogen granules structures are appar ent. Particularly, swelling of the mitochondria and disruption of mito chondrial cristae was observed as well as formation of large vacuoles arising from zymogen granules and liposome fusion. A significant incre ase of lipid hydroperoxide level in the pancreatic tissue was observed . The purpose of this study was to evaluate the effect of 4-hydroxy-TE MPO-a low-mel-wt superoxide dismutase mimic-in a rat cerulein model of acute pancreatitis, with the expectation that free radical mediated h ydroperoxide formation and tissue damage may be reduced significantly. Twenty-one male Wistar rats were divided into three groups: Group 1 ( n=5) served as a control and was infused iv for 3 h with physiologic s aline. Group 2 (n=8) was infused iv for 3 h with cerulein 10 mu g/kg/h ; and Group 3 (n=8) infused iv both with cerulein and 4-hydroxy-TEMPO 22.6 mg/kg/h. Pancreatic tissue damage was quantified by measuring lip id hydroperoxide (LOOH) level, the weight of the organ, and by light a nd electron microscopic examination. 4-hydroxy-TEMPO penetration acros s cellular membrane barriers was quantified by ESR spectrometric measu rements of 4-hydroxy-TEMPO concentration in pancreatic tissue samples and pancreatic juice as well. Administering 4-hydroxy-TEMPO to rats re sulted in preventing both lipid hydroperoxide formation and severe mor phological damage. 4-hydroxy-TEMPO crossed cellular membrane barriers and was excreted to pancreatic juice. Infusion of 4-hydroxy-TEMPO appe ars to prevent pancreatic injury caused by free radicals in experiment al cerulein pancreatitis.