In an effort to elucidate factors that determine the severity of an attack of acute pancreatitis, we have quantitated the extent of necrosis and of apoptosis in five different models of experimental acute pancreatitis. Severe pancreatitis was induced by obstructing the opossum common bile-pancreatic duct, by administering to mice 12 hourly injections of a supramaximally stimulating dose of caerulein, and by feeding young female mice a choline-deficient, ethionine-supplemented diet. In each of these models of severe pancreatitis, marked necrosis but very little apoptosis was found. Mild pancreatitis was induced by obstructing the rat common bile-pancreatic duct and by infusing rats with a supramaximally stimulating dose of caerulein. In contrast to our findings in severe pancreatitis, mild pancreatitis was characterized by very little necrosis but a high degree of apoptosis. Our finding that the severity of acute pancreatitis is inversely related to the degree of apoptosis suggests that apoptosis may be a teleologically beneficial response to acinar cell injury in general and especially in acute pancreatitis.

The subcellular distribution of the lysosomal enzymes cathepsin B and D in the pancreas was evaluated in rats infused with saline (control) or a maximal (0.25 microgram . kg-1 . h-1) or a supramaximally stimulating dose (5 micrograms . kg-1 . h-1) of the secretagogue caerulein. The latter results in acute edematous pancreatitis, inhibition of digestive enzyme secretion, and the localization of digestive zymogens in organelles whose fragility has been increased by caerulein infusion [A. Saluja et al. Am. J. Physiol. 249 (gastrointest. Liver Physiol. 12): G702-G710, 1985]. Samples from control animals were found to have 29.9 +/- 1.8% of the cathepsin B activity in the pellet centrifuged at 1,300 g for 15 min (containing primarily zymogen granules) and 54.7 +/- 2.5% in the pellet centrifuged at 12,000 g for 12 min (containing primarily lysosomes and mitochondria). After supramaximal stimulation with caerulein for 3.5 h the pellet centrifuged at 1,300 g for 15 min had 55.1 +/- 2.5%, and the pellet centrifuged at 12,000 g for 12 min had 30.6 +/- 2.0% of cathepsin B activity. This redistribution was time dependent, noted within 1 h of starting caerulein infusion, and maximal after 2.5 h of infusion. Electron microscopic immunolabeling studies revealed localization of cathepsin D in discrete organelles that, in the samples from animals infused with a supramaximally stimulating dose of caerulein, were larger, more abundant, and more concentrated in the pellet centrifuged at 1,300 g for 15 min than in the controls. During infusion with supramaximal doses of caerulein, the cathepsin B-containing organelles were found to become progressively more fragile.(ABSTRACT TRUNCATED AT 250 WORDS)

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Infusion of a supramaximal dose of caerulein results in acute interstitial pancreatitis in rats. We report studies of in vivo pancreatic acinar cell function during the initial 3.5 h of supramaximal stimulation with caerulein (5 micrograms X kg-1 X h-1). Amino acid [( 3H]phenylalanine) uptake was not altered, and there was no change in the rate or extent of protein synthesis or in intracellular transport of in vivo pulse-labeled proteins from microsome to zymogen granule-enriched fractions. However, the discharge of labeled protein was markedly inhibited. Radioautographic studies indicated that the pulse-labeled proteins retained in the gland were not located extracellularly but had accumulated within acinar cells, with a preferential distribution at the cell apex (presumably in zymogen granules) and in large vacuoles that form within the cell during hyperstimulation. Supramaximal stimulation with caerulein also caused increasing amounts of amylase and labeled proteins to be recovered in the postmicrosomal fraction. These findings suggest that supramaximal stimulation causes digestive enzymes to become localized in organelles that are fragile and subject to disruption during tissue homogenization. These organelles may be the vacuoles noted in morphological studies and believed to represent immature condensing vacuoles and/or crinophagic vacuoles.

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