The pathogenesis of chemically induced pancreatic injury

The colocalization theory of pancreatitis states that activation of trypsinogen within crinophagic vacuoles leads to acute pancreatitis. The purposes of this study were to examine the toxic effects of three chemicals on the pancreas and identify crinophagic vacuoles by using immunocytochemical techniques. The models studied included an experimental butyrophenone tranquilizer (MDL 17,214) in the hamster, an organophosphate insecticide (Diazinon) in the guinea pig and zinc in the duckling. Additionally, the morphology of duckling pancreas recovering from zinc toxicosis was examined for 7 to 21 d after zinc was removed from the diet. In the hamster, MDL 17,214 when dosed orally, caused lethargy and strabismus at 14 d in the high dose group. No gross or microscopic lesions were observed in the pancreas. Guinea pigs were dosed with 25-175 mg/kg of Diazinon intravenously. Animals dosed with $\ge$125 mg/kg intravenously developed signs of organophosphate toxicosis including tremors, lacrimation, salivation, defecation, urination and dyspnea. In guinea pigs dosed with $\ge$150 mg/kg i.v., acinar cells were degranulated at 6 hr. and vacuolar degeneration was observed at 24 and 48 hr. in 14 of 25 surviving animals. Supranuclear, clear, round to oval vacuoles occasionally contained membranous whorls and electron dense debri. Vacuoles were typically located adjacent to the Golgi, as is reported in cholinergic stimulation in the dog and cerulein stimulation in the rat. Cells with vacuoles were not seen in sections from animals killed 72 hours after dosing. High mortality (22/47) in affected dose groups ($\ge$150 mg/kg i.v.) diminished the usefulness of the model in exploring organophosphate induced pancreatic injury. Ducklings fed 2500 ppm zinc for up to 10 days had no gross pancreatic lesions. Ultrastructurally, proliferation of the Golgi complex was observed at 12 hr., and vesiculation of the limiting membrane of condensing vacuoles and immature zymogen granules was observed at 24 hours. Zymogen granules were vacuolated at 36 hr., and clear autophagic vacuoles appeared at 48-72 hours. Autophagic vacuoles, positive for acid phosphatase and trypsinogen were observed at 96 hours, as were heterophagic vacuoles which contained remnants of apoptotic cells. The findings suggested that abnormal maturation of zymogen granules resulted in autophagy of redundant membranes and protein. The relative concentrations of lysosomal and digestive enzymes favored catabolism rather than activation of trypsinogen. In ducklings fed zinc for 10 days, pancreatic lesions included marked vacuolar degeneration and slight periacinar fibrosis. Pancreata from animals fed the control diet for 7 to 21 days after being fed zinc, had normal, but fewer zymogen granules within the apical cytoplasm. Frequent condensed phagolysosomes, or dense bodies, were located along the basolateral plasmalemma at 7 and 14 days, but they were rare at 21 days