Although a relevant animal model is essential for studying human diseases, one has yet to be established for mouse pancreatitis. Early non-invasive models of mouse pancreatitis have serious limitations.

In this study, we compared the efficiency, consistency, and reproducibility of inducing pancreatitis in 3 non-invasive mouse models of pancreatitis in Wistar albino mice: (1) L-arginine-induced model (2 intraperitoneal injections of 4 g/kg body weight of L-arginine spaced 1 h apart), (2) caerulein-induced model (6 intraperitoneal injections of 50 µg/kg body weight of caerulein at hourly intervals), and (3) caerulein + LPS (lipopolysaccharide)-induced model (6 intraperitoneal doses of 50 µg/kg body weight of caerulein at hourly intervals, along with an LPS [10 mg/kg body weight] injection immediately after the last caerulein injection).

Our findings showed that the L-arginine-induced model was inconsistent. The levels of the pancreatic enzymes, amylase and lipase, were higher in the caerulein and caerulein + LPS groups. Histological examination showed tissue destruction in the induced groups, with varying degrees of fibrosis in the caerulein + LPS group.

The caerulein + LPS model was the most reliable model in Wistar albino mice. Our findings may be useful in helping investigators choose the most appropriate animal model for pancreatitis research.

Plasma amino acid levels are altered upon many pathological conditions including acute pancreatitis. It is unclear whether amino acids can be used as specific biomarker of acute pancreatitis severity or recovery. Development of acute pancreatitis is associated with mitochondrial dysfunction and decreased cytosolic ATP level. Sodium pyruvate is considered as a potential treatment of pancreatitis due to its ability to sustain mitochondrial oxidative and ATP-productive capacity in vitro. This study investigated the effect of sodium pyruvate on pancreatic morphology and plasma amino acid levels in rats with acute pancreatitis. Acute pancreatitis in rats was induced by administration of L-arginine (5 g/kg) Experimental treatment group received sodium pyruvate (1 g/kg) for 4 days. On day 8 of the experiment, animals were killed, blood was collected and plasma amino acid concentration was determined with high-performance liquid chromatography. Histological examination showed large areas of fibrosis in the pancreas of animals treated with L-arginine irrespectively of sodium pyruvate administration. Sodium pyruvate improved the plasma amino acid levels. Rats with acute pancreatitis had significantly lower levels of most essential and non-essential amino acids and increased glutamate and aspartate in plasma. Administration of sodium pyruvate completely or partially restored the levels of methionine, phenylalanine, tryptophan, leucine, isoleucine, aspartate, asparagine and ornithine levels, while increasing glutamine and serine to levels significantly higher than control. Plasma lysine, alanine, arginine and taurine remained unaffected in all experimental groups. Sodium pyruvate may be considered for use as a maintenance therapy in acute pancreatitis.

Living organisms respond to physical, chemical, and biological threats with a potent inflammatory response which alters organ cell signaling and leads to dysfunction. We evaluated the therapeutic effect of bone marrow-based mesenchymal stromal cell (BM-MSC) transplanted in rats to preserve tissue integrity and to restore homeostasis and function in the pancreatitis experimental pattern.

This study involved 40 adult male Wister rats. Repeated L-arginine injections caused chronic pancreatitis (CP), leading to the development of pancreatic damage and shifting the intracellular signaling pathways. Rats were then infused with BM-MSC labeled with PKH26 fluorescent linker dye for 12 weeks.

Cell-surface indicators of BM-MSCs such as CD 90 and CD29 were expressed with the lack of CD34 expression. BM-MSC treatment considerably improved the alterations induced in a series of inflammatory markers, including IL-18, TNF-α, CRP, PGE2, and MCP-1. Furthermore, improvement was found in digestive enzymes and lipid profile with amelioration in myeloperoxidase activity. BM-MSC treatment also regulated the (TGF-/p-38MPAK/SMAD2/3) signaling factors that enhances repair of damaged pancreatic tissue, confirmed by reversed alteration of histopathological examination.

our results further bring to light the promise of cell transplant therapy for chronic pancreatitis.

Acute pancreatitis is a potentially severe inflammatory disease that may be associated with a substantial morbidity and mortality. Currently there is no specific treatment for the disease, which indicates an ongoing demand for research into its pathogenesis and development of new therapeutic strategies. Due to the unpredictable course of acute pancreatitis and relatively concealed anatomical site in the retro-peritoneum, research on the human pancreas remains challenging. As a result, for over the last 100 years studies on the pathogenesis of this disease have heavily relied on animal models. This review aims to summarize different animal models of acute pancreatitis from the past to present and discuss their main characteristics and applications. It identifies key studies that have enhanced our current understanding of the pathogenesis of acute pancreatitis and highlights the instrumental role of animal models in translational research for developing novel therapies.

Pancreatic acinar cells require high rates of amino acid uptake for digestive enzyme synthesis, but excessive concentrations can trigger acute pancreatitis (AP) by mechanisms that are not well understood. We have used three basic natural amino acids L-arginine, L-ornithine, and L-histidine to determine mechanisms of amino acid-induced pancreatic injury and whether these are common to all three amino acids. Caffeine markedly inhibited necrotic cell death pathway activation in isolated pancreatic acinar cells induced by L-arginine, but not L-ornithine, whereas caffeine accelerated L-histidine-induced cell death. Both necroptosis inhibitors of RIPK1 and RIPK3 and a necroptosis activator/apoptosis inhibitor z-VAD increased cell death caused by L-histidine, but not L-arginine or L-ornithine. Cyclophilin D knock-out (Ppif-/-) significantly attenuated cell death induced by L-histidine, but not L-arginine, or L-ornithine. Allosteric modulators of calcium-sensing receptor (CaSR) and G-protein coupled receptor class C group 6 member A (GPRC6A) had inhibitory effects on cell death induced by L-arginine but not L-ornithine or L-histidine. We developed a novel amino acid-induced AP murine model with high doses of L-histidine and confirmed AP severity was significantly reduced in Ppif-/- vs. wild type mice. In L-arginine-induced AP neither Ppif-/-, caffeine, or allosteric modulators of CaSR or GPRC6A reduced pancreatic damage, even though CaSR inhibition with NPS-2143 significantly reduced pancreatic and systemic injury in caerulein-induced AP. These findings demonstrate marked differences in the mechanisms of pancreatic injury induced by different basic amino acids and suggest the lack of effect of treatments on L-arginine-induced AP may be due to conversion to L-ornithine in the urea cycle.

The nonneoplastic diseases of the human pancreas generally comprise the inflammatory and degenerative conditions that include acute and chronic pancreatitis, with cystic fibrosis being arguably one of the most important diseases that induce the condition. Both acute and chronic conditions vary in severity, but both can be life threatening; and because of this fact, the study of their progression, and their responsiveness to therapy, is largely conducted by indirect means using serum markers of damage and repair such as amylase and lipase activities that normally occur at very low levels in the circulation but can be significantly increased during inflammatory episodes. Progress in the understanding the pathogenesis of both conditions has therefore been largely due to time course studies in animal models of pancreatitis, and it is in this context that animal model development has been so significant. In general terms, the animal models can be divided into the invasive, surgical procedures, and those induced by the administration of chemical secretagogues that induce hypersecretion of the pancreatic enzymes. The former include ligation and/or cannulation of the biliopancreatic ducts with infusion of solutions of various kinds, or the formation of closed duodenal loops. Secretagogue administration includes administration of caerulein or l-arginine in various protocols. An additional model involves administration of dibutyltin dichloride, which induces a partial blockage of the pancreatic ducts to induce pancreatic disease through enzymic reflux into the gland. The models have been invaluable in generating testable hypotheses for the human diseases. These hypotheses for the production of cellular damage as the initiating events in the disease include (1) intracellular chemical activation, (2) pancreatic secretion reflux, (3) intracellular production of reactive oxygen species, and (4) intracellular production of free radicals.

To determine whether tacrolimus administered to rats, in the presence of pancreatitis induced by L-Arginine, interferes with the serum levels of amylase and glucose and the histological pattern of the pancreatic parenchyma.

Forty Wistar rats were divided into four groups with 10 rats each: control group (C), tacrolimus group (T), pancreatitis group (P) and pancreatitis-tacrolimus group (PT). We evaluated serum levels of amylase, glucose, and tacrolimus and made histological assessments of the pancreas. Induction of pancreatitis was made by inoculation of L-Arginine at a dose of 500 mg/100g body weight intraperitoneally, and tacrolimus treatment at a dose of 1ìg/kg subcutaneously for four days.

Serum amylase was higher (p = 0.0000) in groups PT, P and T than in the control group. The PT group mean was higher (p = 0.0009) than in the T group, but did not differ (p = 0.6802) from the average of the P group. There was no difference between groups P and T (p = 0.2568). Neither in mean blood glucose between the groups (p = 0.4920); serum levels of tacrolimus were similar in PT and T groups (p = 0.7112). There were no histological changes in groups T and C and no hemorrhage in the pancreas of rats in groups P and PT. In group P, there was no edema in 30%, mild edema in 20% and in 50%, moderate; as for inflammatory infiltration, it was moderate in 80% and absent in 20%, and atrophy of the parenchyma was moderate in 60% and severe in 40%. In the PT group, there was edema, inflammatory infiltration or atrophy in the pancreas in all rats.

Treatment with Tacrolimus induced an increase in serum amylase in normal mice, but did not affect blood glucose or the histological pattern of the pancreatic parenchyma. In the presence of pancreatitis induced by L-Arginine tacrolimus induced edema, inflammatory infiltration and more severe atrophy in the pancreatic parenchyma.

We established the WBN/Kob-Lepr(fa) rat as a new congenic strain for the fa allele of the leptin receptor gene (Lepr). Homozygous (fa/fa) WBN/Kob-Lepr(fa) rats provide a model of non-insulin-dependent diabetes, although its onset is secondary to pancreatitis. In the present study, we compared histopathological observations of pancreatitis in each genotype of this rat, to examine its suitability as a model of pancreatitis. The histopathological findings of the pancreatitis revealed intense changes dependent on age, such as hemorrhage or hemosiderin deposition. The pancreatitis in homozygous (fa/fa) WBN/Kob-Lepr(fa) rats were more severe than those of WBN/Kob rats.

Reactive oxygen and reactive nitrogen species (ROS/RNS) have been implicated in the pathogenesis of acute and chronic pancreatitis. Clinical and basic science studies have indicated that ROS/RNS formation processes are intimately linked to the development of the inflammatory disorders. The detrimental effects of highly reactive ROS/RNS are mediated by their direct actions on biomolecules (lipids, proteins, and nucleic acids) and activation of proinflammatory signal cascades, which subsequently lead to activation of immune responses. The present article summarizes the possible sources of ROS/RNS formation and the detailed signaling cascades implicated in the pathogenesis of pancreatic inflammation, as observed in acute and chronic pancreatitis. A therapeutic ROS/RNS-scavenging strategy has been advocated for decades; however, clinical studies examining such approaches have been inconsistent in their results. Emerging evidence indicates that pancreatitis-inducing ROS/RNS generation may be attenuated by targeting ROS/RNS-generating enzymes and upstream mediators.

The pancreas is the primary organ responsible for the digestion of food. Pancreatic acinar cells are specialized for the production of digestive enzymes, and these cells have a higher rate of protein synthesis than all other adult human tissues. Digestive enzymes are produced in the endoplasmic reticulum (ER), a multifunctional organelle responsible for the synthesis and correct folding of proteins in the secretory pathway. Disturbances of ER function lead to stress-response mechanisms that can restore homeostasis but can also, if uncontrolled, cause disease. Pancreatic acinar cells are particularly susceptible to ER perturbations, and mechanisms that relieve ER stress are necessary for normal pancreatic development. Furthermore, ER stress occurs during acute pancreatitis, and may also be present in pancreatic cancer. However, the specific roles of ER stress-response mechanisms in these diseases are unknown.

The authors investigated the role of activated perilobular, not periacinar, pancreatic stellate cells, in fibrogenesis in chronic pancreatitis, based on the distribution of myofibroblasts. Twenty-four patients with clinically diagnosed chronic alcoholic pancreatitis were studied histopathologically, immunohistochemically and quantitatively. In all cases, fibrosis was patchily distributed in the perilobular, or interlobular, areas, accompanied by a cirrhosis-like appearance; it had extended into the intralobular area in advanced cases. Seven patients had a massive or confluent loss of exocrine tissue, resulting in extensive interlobular fibrosis; the more extensive the interlobular fibrosis, the smaller the lobules. Immunoreactivity to alpha-smooth muscle actin, a myofibroblast marker, was found mostly in the same areas of the fibrosis, mainly the interlobular, and less often the periacinar, areas; the average percentage area of perilobular myofibroblasts was significantly higher than that of periacinar myofibroblasts in 20 randomly selected lobules (P > 0.001), in which the average value for the former was 38.03% (range: 13.54-61.32%; SD, 13.8%) and that for the latter was 4.85% (range 0.90-9.57%; SD, 2.22%). Fibrosis also immunostained positive for collagen types I and III. In conclusion, activated perilobular, not periacinar, pancreatic stellate cell contribute to fibrogenesis in chronic pancreatitis.

Acute pancreatitis (AP) is characterized by edema, acinar cell necrosis, hemorrhage, and severe inflammation of the pancreas. Patients with AP present with elevated blood and urine levels of pancreatic digestive enzymes, such as amylase and lipase. Severe AP may lead to systemic inflammatory response syndrome and multiorgan dysfunction syndrome, which account for the high mortality rate of AP. Although most (>80%) cases of AP are associated with gallstones and alcoholism, some are idiopathic. Although the pathogenesis of AP has not yet been elucidated, a common feature is the premature activation of trypsinogen within pancreatic tissues, which triggers autodigestion of the gland. Recent advances in basic research suggest that etiologic factors including cyclooxygenase-2, substance P, and angiotensin II may have novel roles in this disease. Basic research data obtained thus far have been based on animal models of AP ranging from mild edematous pancreatitis to severe necrotizing pancreatitis. In view of this, an adequate selection of experimental animal models is of paramount importance. Notwithstanding these animal models, it should be emphasized that none of these models mimic the clinical situation where varying degrees of severity usually occur. In this review, commonly used animal models of AP will be critically evaluated. A discussion of recent advances in our knowledge about AP risk factors is also included.

The underlying mechanisms involved in the pathogenesis of acute pancreatitis are ill understood. The mortality rate of this disease has not significantly improved over the past few decades. Current treatment options are limited, and predominantly aimed at supportive therapy. A key feature of severe acute pancreatitis is the presence of extensive tissue necrosis with both local and systemic manifestations of inflammatory response syndromes. A better understanding of the underlying pathophysiology of severe acute pancreatitis may lead to more targeted therapeutic options, potentially leading to improved survival. Animal models of acute pancreatitis are therefore an essential investigative tool for these aims to be achieved. This review discusses the suitability of recent non-invasive models of acute pancreatitis such as hormone-induced, alcohol-induced, immune-mediated, diet-induced, gene knockout and L-arginine; and invasive models including closed duodenal loop, antegrade pancreatic duct perfusion, biliopancreatic duct injection, combination of secretory hyperstimulation with minimal intraductal bile acid exposure, vascular-induced, ischaemia/reperfusion and duct ligation.

Despite medical treatment, the lethality of severe acute pancreatitis is still high (20-30%). Therefore, it is very important to find good animal models to characterise the events of this severe disease. In 1984, Mizunuma et al. developed a new type of experimental necrotizing pancreatitis by intraperitoneal administration of a high dose of L-arginine in rats. This non-invasive model is highly reproducible and produces selective, dose-dependent acinar cell necrosis. Not only is this a good model to study the pathomechanisms of acute necrotizing pancreatitis, but it is also excellent to observe and influence the time course changes of the disease. By writing this review we illuminate some new aspects of cell physiology and pathology of acute necrotizing pancreatitis. Unfortunately, the reviews about acute experimental pancreatitis usually did not discuss this model. Therefore, the aim of this manuscript was to summarise the observations and address some challenges for the future in L-arginine-induced pancreatitis.

There are many experimental models for chronic pancreatitis. However, it remains unclear which animal models of pancreatic fibrosis can be categorized as chronic pancreatitis models. We compared the histologic features of some animal models of pancreatic fibrosis/chronic pancreatitis and chronic pancreatitis in humans.

Human chronic pancreatitis due to chronic alcohol abuse and unknown etiology showed interlobular fibrosis and a cirrhosis-like appearance. Histopathologically, spontaneous pancreatitis models, WBN/Kob rats and OLETF rats, showed localized/nodular fibrotic lesions, which consisted of swollen, aggregated, atrophic islets of Langerhans; loss of the exocrine parenchyma and hemosiderin deposition that was seldom distributed in the interlobular area. On the other hand, fibrosis in the canine model, which was produced by combining alcohol administration with incomplete pancreatic duct obstruction, was characterized by interlobular fibrosis admixed with a cirrhosis-like appearance very similar to that in human chronic pancreatitis.

Most experimental models for chronic pancreatitis, except alcohol administration combined with other procedures such as incomplete pancreatic duct obstruction, are different from human chronic pancreatitis.

Arginine induced acute pancreatitis was evaluated as a novel and distinct form of experimental pancreatitis with particular attention to the actin cytoskeleton and expression of heat shock or stress proteins. Arginine induced a dose related necrotising pancreatitis in rats, as shown by histological evaluation, and an increase in serum amylase. Severe pancreatitis induced by 4.5 g/kg arginine was accompanied by dramatic changes in the actin cytoskeleton, as visualised with rhodamine phallodin. Intermediate filaments were also disrupted, as visualised by cytokeratin 8/18 immunocytochemistry. Arginine pancreatitis was accompanied by a stress response with a large increase in the small heat shock protein HSP27, as well as HSP70, peaking at 24 hours and localised to acinar cells. There was a lower increase in HSP60 and HSP90 and no effect on GRP78. HSP27 was also shifted to phosphorylated forms during pancreatitis. A lower dose of arginine (3.0 g/kg) induced less pancreatitis but a larger increase in HSP70 and HSP27 expression and phosphorylation of HSP27. Thus HSP expression can be overwhelmed by severe damage. The present work in conjunction with earlier work on caerulein induced pancreatitis indicates that changes in the actin cytoskeleton are an early component in experimental pancreatitis.

In L-arginine (Arg)-induced pancreatitis, evidence of acute inflammation was observed on d 1-3. Continuous tissue atrophy became visible at the sites of previous pancreatic necrosis, with simultaneous regeneration of the pancreas, mainly around the Langerhans islets. Administration of low doses of cholecystokinin-octapeptide (CCK-8) increased the inflammatory signs of pancreatitis in the early phase, but subsequently diminished the level of atrophy and accelerated the processes of regeneration in this model of pancreatitis.

The aim of this work was to study the regenerative processes following Arg-induced pancreatitis in rats. Besides the spontaneous regeneration, the effects of low doses of CCK-8 on the laboratory and morphologic parameters in this type of experimental pancreatitis were investigated.

Male Wistar rats were divided into three groups. In group I, the rats received 200 mg/100 g body weight of Arg i.p. twice, at an interval of 1 h, and 0.5 mL saline was administered s.c. twice daily. In group II, besides the same amount of Arg, the rats received 1 microgram/kg of CCK-8 s.c. in 0.5-mL saline twice daily (7 AM and 7 PM). In the control animals (group III), an identical amount of glycine was administered i.p. instead of Arg at the same times. The rats were examined on d 1, 3, 7, 14, and 28 after pancreatitis induction. The pancreatic weight/body weight ratio (pw/bw) was calculated in each case. The serum levels of amylase, and glucose and the pancreatic contents of soluble protein, trypsin, amylase and DNA were determined, and histologic examinations were performed.

In groups I and II, both pw/bw (3.5 +/- 0.2 mg/g and 4.1 +/- 0.28 mg/g, respectively) and the serum amylase level (8900 +/- 560 IU/L and 11100 +/- 1390 IU/L, respectively) were significantly elevated on d 1 vs group III (2.1 +/- 0.06 mg/g and 5562 +/- 373 IU/L, respectively). Pw/bw was significantly decreased in groups I (0.96 +/- 0.12 mg/g, 0.8 +/- 0.1 mg/g, and 1.8 +/- 0.1 mg/g, respectively) and II (1.4 +/- 0.15 mg/g, 1.7 +/- 0.2 mg/g, and 1.95 +/- 0.1 mg/g, respectively) on d 7, 14, and 28 vs group III (2.6 +/- 0.3 mg/g, 3.1 +/- 0.15 mg/g, and 2.7 +/- 0.1 mg/g, respectively), whereas in group II it was significantly elevated vs. group I on d 7 and 14. The pancreatic contents of soluble protein, DNA, trypsin and amylase were significantly decreased on d 3-14 in groups I and II vs group III. The pancreatic DNA level was significantly elevated in group II (1.23 +/- 0.2 mg/pancreas) vs group I (0.7 +/- 0.1 mg/pancreas) on d 7. In group II, the soluble protein (73.1 +/- 15.5 mg/pancreas) and amylase (1104 +/- 160 IU/pancreas) levels were significantly elevated on d 14 as was that of trypsin (27.2 +/- 3.1 IU/pancreas) on d 28, vs group I (26.4 +/- 5.3 mg/p, 525 +/- 111 IU/pancreas, and 16.3 +/- 1.1 IU/pancreas, respectively). On histologic sections, the signs of acute inflammation of the pancreas were more pronounced in group II than in group I on d 1-3. After that time, in spite of the progressive atrophy of the pancreas, the signs of tissue repair were more expressed in group II.

In order to elucidate the relationship of cholecystokinin to acinar cell regeneration, the current study examined the changes in plasma cholecystokinin and immunostaining of proliferating cell nuclear antigen in the pancreas of rats with acute necrotizing pancreatitis. Proliferating cell nuclear antigen immunohistochemistry has been used to examine the proliferation of cells in several types of tissues. We compared the usefulness of proliferating cell nuclear antigen immunostaining and the incorporation of 5-bromodeoxyuridine to demonstrate acinar cell proliferation in the pancreas of rats with acute necrotizing pancreatitis. We also examined the relationship between these labeling indices and plasma cholecystokinin concentrations. The labeling index of paraformaldehyde-fixed specimens stained with proliferating cell nuclear antigen showed biphasic peaks at 12 hr and day 7. On the other hand, the methanol-fixed specimens stained with proliferating cell nuclear antigen and specimens stained with bromodeoxyuridine showed monophasic peaks in their labeling indices on day 5. There was a linear correlation (r = 0.808, P < 0.001) between the labeling index of bromodeoxyuridine and that of methanol-fixed proliferating cell nuclear antigen during the entire experimental period. During the regenerating phase, plasma cholecystokinin bioactivity showed positive correlations with the labeling index of bromodeoxyuridine and that of methanol-fixed proliferating cell nuclear antigen, r = 0.555 and 0.566, respectively (P < 0.001). Immunostaining of methanol-fixed proliferating cell nuclear antigen may be a useful tool for analyzing proliferating acinar cells. Acinar cell proliferation correlates with the bioactivity of plasma cholecystokinin during the regenerating phase of acute pancreatitis.

Two similar cohorts of low birth weight infants whose size was appropriate for gestational age randomly received either aztreonam-arginine plus ampicillin (n = 15) or gentamicin plus ampicillin (n = 15) for empiric treatment of neonatal sepsis. The regimens were infused together with glucose at greater than 5 mg/kg per minute, and immediate (4 hours) and cumulative (3 days) effects were assessed. Serum arginine and insulin values rose immediately after administration of aztreonam (containing 0.15 mmol of arginine per kilogram), but there were no changes in the gentamicin-treated cohort; no differences occurred in either cohort in serum concentrations of glucose, ammonia, potassium, creatinine, and bilirubin. After 3 days of antibiotic therapy (n = 13), the baseline serum arginine concentration was almost twice as high in the aztreonam group and showed a similar further rise and fall during the 4 hours after infusion; arginine urinary fractional excretion (normalized to creatinine clearance) decreased in the gentamicin group. The indirect bilirubin concentration rose more (p less than 0.001) in the aztreonam-treated infants (5.1 to 11.5 mg/dl (87 to 196 mumol/L] than in the gentamicin-treated infants (5.5 to 8.1 mg/dl (94 to 138 mumol/L)). Thus a modest differential bilirubin response and modestly elevated baseline serum arginine level occurred after the 3-day low-arginine doses of this study; serum ammonia and glucose concentrations were not affected. Aztreonam-arginine in neonates was well tolerated metabolically, and we believe that it can be used safely in conjunction with attention to glucose and bilirubin metabolism.

We examined the biological and histologic characteristics of a new experimental model of acute necrotizing pancreatitis induced by excessive doses of arginine in rats. Rats were given a single intraperitoneal injection of 500 mg/100 g body weight of L-arginine. At 12-24 hr after the arginine injection, serum levels of amylase, lipase, and anionic trypsin(ogen) reached respective peak values 2, 5, and 20 times those of control rats without arginine and returned to control levels after 24-48 hr. The contents of pancreatic protein, DNA, and digestive enzymes were markedly reduced after the arginine injection and reached their nadirs at 72 hr. After 14 days these levels were almost normal. Histologic examination revealed a number of small vesicles within acinar cells at 6 hr, which were identified as markedly swollen mitochondria by the electron microscope. Other intracellular organelles and nuclei also showed degenerative changes. At 12 hr interstitial edema appeared, and acinar cell necrosis was seen after 24 hr. The extent and severity of necrotic changes of pancreatic exocrine tissue with inflammatory cell infiltration were maximal at 72 hr. At seven days, pancreatic acinar cells began to regenerate, and pancreatic architecture appeared almost normal after 14 days. The present study has demonstrated that the administration of excessive doses of arginine induces a new, noninvasive experimental model of acute necrotizing pancreatitis.

Intraperitoneal injection of lysine (400 mg/100 g body weight) in rats caused necrosis of pancreatic acinar cells with fat necrosis and a significant increase in serum amylase and lipase. The early morphological changes in the pancreas were investigated. At 3 to 6 h, marked swelling of mitochondria was observed throughout the cytoplasm followed later by dilation of the endoplasmic reticulum and the formation of autophagic vacuoles, indicative of rapid cellular degeneration. These results suggest that transient disturbance of energy formation following mitochondrial swelling resulted in disorders of protein metabolism, with disorganization of the endoplasmic reticulum and pyknosis of the nuclei as later events.

The effect of nutrition on the incidence of pancreatic damage was studied. Injection of excess arginine was found to cause more massive necrosis of the acinar cells after 24 h in malnourished rats (those given 50 g casein/kg diet) than in well-nourished rats (those given 200 g casein/kg diet). Ultrastructural examination showed that whorl formation of the endoplasmic reticulum, decreases in the number of zymogen granules and formation of vacuoles in the cytoplasm were more marked in rats given 50 g casein/kg diet. Degradation of zymogen granules within vacuoles in the damaged cells was frequently observed in rats given 200 g casein/kg diet. Necrosis of adipose tissue was associated with pancreatic damage more frequently in rats given 200 g casein/kg diet; rats with large amounts of zymogen granules in the acinar cells showed particularly severe necrosis of adipose tissue. Rats given 50 g casein/kg diet did not show necrosis of adipose tissue. These results indicate that in the malnourished state there were more marked arginine lesions of the pancreas in which to study cellular and histologic changes than in the well-nourished state and that the occurrence of necrosis of adipose tissue may be related to a high content of zymogen granules in the acinar cells before pancreatic damage.