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Leukocyte activation, inflammatory up-regulation, and microcirculatory disruption associated with ischemia-reperfusion injury are hallmarks in the pathogenesis of acute pancreatitis (AP). NO donors ensure microvascular integrity, while glucocorticoids act as anti-inflammatory and immune modulator drugs. AP was induced by the biliopancreatic duct outlet exclusion-closed duodenal loops (BPDOE-CDLs) model. Treatment with hydrocortisone (6 mg/kg) or prednisolone (0.5 mg/kg) alone or together with DETA-NO (0.5 mg/kg) was done (a)1 hr pre or (b)1 hr post, or (c) 1 hr pre and 4 hr post ,or (d) 4 hr post triggering AP. NOS inhibition by L-NAME (15 mg/kg) and glucocorticoid receptor blockage by mifepristone (3 mg/kg) was considered. AP severity was assessed by biochemical and histopathological analyses. Treatment with glucocorticoids together with DETA-NO 1 hr pre and 4 hr post BPDOE-CDLs reduced serum amylase, lipase, C-reactive protein, IL-6, IL-10, hsp72, and 8-isoprostane as well as pancreatic and lung myeloperoxidase. Acinar and fat necrosis, hemorrhage, and neutrophil infiltrate were also decreased. Hydrocortisone together with DETA-NO rendered the best results. We conclude that AP severity was significantly diminished by glucocorticoids associated with DETA-NO, with the optimal dose and time point of administration being crucial to provide adequate protection against AP.

Aim: To investigate the severity of acute pancreatitis (AP) is associated to the intensity of leukocyte activation, inflammatory up-regulation and microcirculatory disruption associated to ischemia-reperfusion injury. Microvascular integrity and inhibition of pro-inflammatory mediators are key-factors in the evolution of AP. Relaxin is an insulin-like hormone that has been attributed vasorelaxant properties via the nitric oxide pathway while behaving as a glucocorticoid receptor agonist., Methods: AP was induced by the bilio-pancreatic duct-outlet-exclusion closed-duodenal-loops model. Treatment with relaxin was done at different time-points. Nitric oxide synthase inhibition by L-NAME and glucocorticoid receptor (GR) blockage by mifepristone was considered. AP severity was assessed by biochemical and histopathological analyses., Results: Treatment with relaxin reduced serum amylase, lipase, C-reactive protein, IL-6, IL-10, hsp72, LDH and 8-isoprostane as well as pancreatic and lung myeloperoxidase. Acinar and fat necrosis, hemorrhage and neutrophil infiltrate were also decreased. ATP depletion and ADP/ATP ratio were reduced while caspases 2-3-8 and 9 activities were increased. L-NAME and mifepristone decreased the efficiency of relaxin., Conclusion: Relaxin resulted beneficial in the treatment of AP combining the properties of a GR agonist while preserving the microcirculation and favoring apoptosis over necrosis.

Microcirculatory disturbances and leukocyte activation are main events in the pathogenesis of acute pancreatitis (AP) that is characterized by inflammatory up-regulation. Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) regulate vascular function and mitigate inflammation. To investigate the influence of NO-NSAIDs on AP. AP was induced by the biliopancreatic duct outlet exclusion-closed duodenal loops model. Treatment with NO-flurbiprofen, NO-ibuprofen, NO-aspirin, or their parental drugs was done (i) 1 h before, (ii) 1 h after, (iii) 1 h before and 4 h after, or (iv) 4 h after surgery. The degree of severity was evaluated using biochemical and histopathological analyses. NO-NSAIDs given before and during the first hour of the noxia decreased blood levels of amylase, lipase, C-reactive protein, IL-6, IL-10, heat shock protein 72, prostaglandin E2 inactive metabolite, and 8-isoprostane, as well as pancreatic and lung myeloperoxidase and cyclooxygenase. Acinar and fat necrosis, hemorrhage, and leukocyte infiltrate were also reduced. The best protection was achieved when treatment was performed 1 h before and 4 h after triggering AP. NO-flurbiprofen was the most effective drug. AP severity was significantly ameliorated by NO-NSAIDs being the administration time essential to achieve optimal pancreatic protection that may result to be useful in the prevention of postendoscopic severe AP.

Background and Aims: In the general adaptation syndrome, gastric lesions are the first manifestation of stress. We hypothesized that acute pancreatitis (AP), an inflammatory acute disease, will be exacerbated if unchained following stress. Visceral hypersensitivity will be enhanced due to catecholaminergic discharges leading to an over-induction of the intrapancreatic cholinergic tone with increased response of the pancreocyte to cholecystokinin (CCK). Our aim was to investigate the influence of stress before AP on the later AP, and the effect of AP on underlying diseases such as gastric ulceration., Methods: The model of stress induced by restraint was followed by the bilio-pancreatic duct outlet exclusion closed duodenal loops model. The effect of autonomous arc reflex (AAR) interruption by anesthetics after stress but before AP was assessed. The participation of the vagal and sympathetic pathways and involvement of CCK-A receptors were considered. The degree of severity was evaluated using biochemical and histopathological analyses., Results: Induction of AP after stress was more severe than in its absence. Acinar and fat necrosis, hemorrhage and neutrophil infiltrate foci were evenly distributed, being significantly greater in size and number after stress. Gastric ulceration evolved to ulcer, hemorrhage and gastric necrosis after AP triggering. Serum amylase, lipase, C-reactive protein, IL-6, IL-10 and plasmatic hsp72 as well as pancreatic and lung myeloperoxidase were significantly elevated in AP after stress while pancreatic amylase and lipase were significantly reduced. AAR blockage ameliorated AP after stress., Conclusions: Stress aggravates pancreatic pathology while AP deteriorates gastric pathology, and anesthetic treatment was beneficial for both. Restraint in other animal models can be useful to study the influence of stress in the evolution of other diseases., (Copyright 2004 S. Karger AG, Basel and IAP)

Severe acute pancreatitis may be triggered by an extrapancreatic insult at the peri-Vaterian duodenum such as that occurring in the short-term, 20 min closed duodenal loop model in Wistar rat, which mimics biliary acute pancreatitis or that following endoscopy. Glucocorticoids are immunological modulators whose therapeutic value is worth investigating. Wistar male rats were used under standardized conditions. Acute pancreatitis was induced by instillation of a 7% sodium tauraocholate solution with 5 drops of methylene blue to monitor absence of duodenal bilio pancreatic reflux into the peri-Vaterian duodenum for 20 min. Detection of biliopancreatic reflux with methylene blue was an exclusion criterion. Different doses and times of administration of subcutaneous hydrocortisone were evaluated. Biochemical assays were carried out in blood samples and pancreatic and lung tissue, while histpathological studies were done in the pancreas, lung liver, duodenum, spleen, kidneys, suprarenal glands, and stomach. Animals subjected to the experimental model developed severe acute pancreatitis. According to the dose and time of administration, hydrocortisone therapy was effective and beneficial at a dose of 4 mg/kg give 30 min before inducing acute pancreatitis. It was ineffective when doses were <4 mg/kg and given before sodium taurocholate harmful when the dose was >4 mg/kg and given either before or after. Thus, the proposed model is valid and useful to study the initiation mechanism of acute pancreatitis caused extrapancreatically while its amelioration by glucocorticoid is related the dose and time factor to achieve therapeutical results.

Background and Aims: Biliary acute pancreatitis or postendoscopic iatrogenia acute pancreatitis (AP) are likely triggered by autonomous arc reflexes (AAR) initiated in the peri-Vaterian duodenum (PV-D). The bilio-pancreatic duct outlet exclusion closed duodenal loops (BPDOE-CDL) model mimics these circumstances. Our aim was to validate this model and evaluate the role of AAR via their interruption with local anesthetics., Methods: Severe AP was induced in Wistar rats with the BPDOE-CDL model: extra-pancreatic insult was provoked in the PV-D by distension with 8% sodium taurocholate and methylene blue for 45 min to show the absence of duodenum pancreatic reflux. Treated experimental groups received a 2% lidocaine chlorhydrate gel instilled into the PV-D prior to triggering the AP, or before and after at the celiac-ganglia complex, or at both sites. The degree of severity was evaluated using biochemical and histopathological analysis., Results: Induction of AP by BPDOE- CDL was severe, with acinar and fat necrosis and hemorrhage with a greater foci number in the cephalic segment. Groups pretreated with local anesthetic developed mild or moderate AP characterized by edema and leukocyte infiltrate. Serum amylase, lipase and CRP were significantly reduced in all treated groups. Other blood metabolites and pancreatic myeloperoxidase, amylase and lipase, were significantly decreased., Conclusion: The BPDOE-CDL model was validated, emphasizing the importance of AAR as extrapancreatic initiators of AP. The interruption of AAR by lidocaine chlorhydrate prevented excessive pancreatic inflammation and diminished hemorrhage and necrosis and may prove a useful prophylactic procedure to prevent postendoscopic severe AP., (Copyright 2003 S. Karger AG, Basel and IAP)

Introduction: The process of pancreatic regeneration, well known and accepted, is less known than the hepatic and includes different mechanisms and factors. Pancreatic regeneration is better known in acute pancreatitis. After an extensive pancreatic necrosis, the morphological and functional regeneration is assessed by dynamic computed tomography associated with normalization of glycemia and the exocrine function. Different groups identified and evaluated experimentally and clinically the actions of multiple factors involved in the process of pancreatic regeneration. Even difficult to assess, pancreatic regeneration after partial pancreatectomy is well documented and of capital importance., Case Report: A 57-year-old woman with discomfort in the upper-left abdominal quadrant. CT scans showed a tumor in the body and tail of the pancreas adherent to the spleen. Preoperative CA 19-9 was normal. She was operated on and the tumor resected en bloc with the spleen. Only the head of the pancreas was preserved. Intraoperative pathological examination of the specimen showed a mucinous cistoadenoma with no malignant degeneration. Postoperative course was uneventful and discharged at p.o. day 10, with ongoing diabetes. Four month later she presented pain in the upper-left quadrant with hyperamylasemia. CT scans showed a normal body and tail with an image of pseudocyst at the top of the pancreatic tail. One year after the initial surgery she remained asymptomatic, without diabetes and with no dietary restrictions. Further CT controls showed images of the entire regeneration of the body and tail of the pancreas., Discussion: Several phenomena are well known and accepted to be associated with the regeneration of the pancreas. In 1965, Tiscornia et al demonstrated the restoration of the pancreatic exocrine function after 6 weeks of selective occlusion of the pancreatic duct. The authors proposed pancreatic regeneration as responsible of morphological, histological and functional changes observed in operated patients where the pancreatic duct was decompressed by an anastomosis to the small bowel and constitutes the rational basis for surgical treatment of chronic pancreatitis. Several humoral factors seems to be involved in pancreatic regeneration acting by a specific receptors-mechanisms, like Bombesin, Octeotride, FGF (Fibroblast Growth Factor) and TGF (Transforming Growth Factor). Friess et al demonstrated increased levels of TGF in acute pancreatitis and considered it to be responsible of the pancreatic regeneration. Waguri et al experimentally demonstrated a double mechanism involved in the regeneration of B-cells: cellular and humoral ways could vary according to different situations. Less evident are the mechanisms involved after surgical pancreatic resection. Kato et al demonstrated the importance of zinc after partial pancreatic resection in dogs. Up to now, there are no other associations experimentally nor in humans. Our case showed in several CT scans control the presence of a normal pancreatic body and tails after a splenopancreatectomy, with restoration of endocrine and exocrine functions. Probably, several mechanisms were involved in this case. Further investigations will elucidate the answered., Conclusions: Pancreatic regeneration was confirmed by CT scans images and also functionally after an extensive resection. Future similar findings could be of great clinical importance.

Luminal proteolytic activity (PA) of different colonic segments was ascertained in animals subjected to pancreatic duct ligation (PDL) and in control rats. The PDL rats revealed a significant PA reduction in the cecum, proximal colon (P < 0.01), and distal colon (P < 0.005). Proteolytic activity, trypsin, and chymotrypsin activity in control rats diminished progressively from the cecum to the distal colon. Conversely in PDL rats, we found maximal PA in distal colon. The conclusion is drawn that a significant proportion of colonic proteolytic activity can be attributed to pancreatic proteases with a maximal contribution at cecum level.

We describe a 65-year-old-man who presented with acute gastrointestinal bleeding secondary to massive submucosal deposits of hyaline material in the small bowel. The histochemical and ultrastructural features of the hyaline substance were typical of lipoid proteinosis, a rare cutaneous disorder in which, to our knowledge, symptomatic compromise of internal organs has not been described previously. The patient was later found to have mild but characteristic mucocutaneous lesions of lipoid proteinosis, as well as asymptomatic deposits in other gastrointestinal sites. Our case documents that severe visceral involvement may occur in lipoid proteinosis, even in previously undiagnosed patients with mild cutaneous manifestations of the disease.

In this work we have demonstrated the influence of a short chain fatty acid (acetate) on the number of enterochromaffin (EC) cells containing serotonin (5HT), at two different pH (pH 6.9 absorptive stimuli, and pH 2.9 secretory stimuli), infused into the colon during one hour. The number of EC cells decrease significatively, specially in the cecum with a solution of low pH (2.9). The action of piprenzepine in preventing this reduction demonstrated that was partly mediated by a cholinergic receptor mechanism. On the other hand, a decrease on the release of 5HT to the lumen was a observed under the influence of pirenzepine. We conclude that the short chain fatty acid acetate, at a low pH induces the release of serotonin through a cholinergic mechanisms indicated by the inhibition observed with antimuscarinic drug.

Background: Fluorescein isothiocyanate-Ulex europeus agglutinin I stain (UEA1) was postulated as a prominent histochemical marker for premalignant mucosa in dimethylhydrazine (DMH)-treated animals. UEA1 (evaluated by two scanning methods) and high iron diamine Alcian blue (HIDAB) stain were used in attempt to detect premalignant colonic mucosa in this animal model. The authors also examined the influence of the duodenal medium on colonic segments transposed to the upper gastrointestinal tract., Methods: Rats were placed into three groups: those with interposed intestine, those receiving the sham operation, and controls. Half of the animals received DMH, and surviving rats were killed at 2, 4, and 8 months., Results: The authors found no differences in tumor development in the transposed and nontransposed colons of animals treated with DMH. Several transposed segments of animals without carcinogen induction showed dysplastic areas. These findings suggest a trophic role of certain duodenal factors in the epithelial kinetics of the transposed colons. The authors did not find HIDAB stain useful in the identification of premalignant colonic mucosa. The quantitative evaluation method of UEA1 binding was more reliable. Fifteen percent of all the colon specimens of animals without chemical induction were stained with UEA1 with this form of evaluation. Positive staining of the interposed colon samples was the most important factor for these findings., Conclusions: In this animal model, UEA1 staining is a potentially useful marker of premalignant mucosa, particularly when the nontransposed distal colon of animals treated with DMH is considered.

An histochemical study has been made of pancreatic biopsies from 5 dogs with gastric and pancreatic Thomas cannulae. 3 dogs received 2 g kg-1 day-1 ethanol for 3, 4 and 48 months; 2 dogs which did not received alcohol served as controls. Acetylcholinesterase has been studied by the histochemical method of Koelle. Choline acetyl transferase by the method of Burt. Our results suggest that there is less acetylcholinesterase activity in the pancreas of alcoholic dogs than in control dogs. This is as more pronounced when the alcohol consumption is prolonged. On the contrary, the intensity of the histochemical reaction for choline acetyl transferase is greater in alcoholic dogs than in controls. Although histochemical methods are only semi-quantitative, these results suggest that the cholinergic tone of the exocrine pancreas is increased in chronic alcoholic dogs. This has already been suggested by previous physiological experiments performed on the same animals.

The earliest change during chronic pancreatitis seems to be precipitation of proteic material consisting apparently of the normal components of pancreatic juice, as demonstrated by pathology studies. Similar changes could be induced in animal experiments. There seems to be a causal relationship between increased protein concentration in pancreatic juice and protein precipitation. The cause of the disease in most cases is alcoholism combined with a diet rich in fat and proteins, or malnutrition in infants. The mechanism of action was clarified in dogs and rats: An increase of cholinergic stimulation influencing pancreatic secretion directly seems to be involved as well as an indirect stimulation of pancreatic secretion by gastroduodenal hormones.

Sequential changes in pancreatic secretion were evaluated during a 2- to 3-year follow-up study in 8 dogs provided with Thomas gastric and duodenal fistulas. Four animals were given intragastric ethanol (2 g kg-1) daily for 3 years; 4 others served as controls. In alcohol-fed animals: (1) Flow rate and bicarbonate output in response to 1 clinical unit kg-1 hr-1 of secretin were increased at the end of 2 years but not after 1 year of alcohol feeding. (2) At the end of 2 years, the dose-response curve of pancreatic secretion to cholecystokinin was unchanged but the maximal bicarbonate and water secretion in response to high doses of secretin were increased. Modifications (1) and (2) are explained by reduplication of pancreatic ducts secondary to the development of chronic pancreatitis, verified by biopsy. (3) The previous report by our group of an increased cholecystokinin release in the course of chronic alcohol consumption in dogs seems to be attributable to an artefact. This work shows that the pancreatic response to intraduodenal oleic acid is not significantly modifed by 3 years of alcohol feeding.

In conscious dogs, provided with gastric and duodenal fistulas (Thomas cannula), the effect of an acute i.v. calcium infusion (10 mg./kg./hr.) on the plateau levels of secretin-induced (GIH, 1 CU./kg./hr.) pancreatic juice parameters were analyzed without or with previous cholingergic blockade by a continuous atropine perfusion (1.5 mg./hr.). In the former condition, i.v. calcium raised all pancreatic juice parameters, mainly protein concentration (148%) and output (173%). During atropine blockade, i.v. calcium changed neither flow rate nor bicarbonate output of secretin-induced pancreatic secretion. On the other hand, i.v. calcium exerted a reduced but still evident effect on protein concentration (85%) and output (40%). Intravenous calcium enhances secretin-induced pancreatic secretion plateau values through two mechanisms, mainly by raising the cholinergic tone of the whole "pancreon" and, partially, through a direct stimulus-secretion coupling effect on the acinar cells. Acute hypercalcemia induces the formation of protein plugs in the pancreatic secretion. They are excreted in the course of many days in both basal and secretin-stimulated pancreatic juice.

As it has been previously shown, the pancreatic secretory response to an intraduodenal infusion of oleic acid is increased in animals accustomed to daily ethanol consumption compared to matched controls. This action has been verified in dogs provided with a Thomas cannula and consuming 2 g kg-1 ethanol or not, daily since 3 years. An intravenous infusion of 0.75 mg kg-1 h-1 of atropine suppresses the difference between alcoholic and non-alcoholic animals. Therefore, the increased release of CCK-PZ in response to meal, which is characteristic of chronic alcoholic animals, is under cholinergic control.

A surgical procedure has been disigned which permits injection in the stomach and the duodenum by separate catheters, collection of the pancreatic juice during the experiments, recirculation of the pancreatic juice into the duodenum between experiments, and a normal circulation of bile in rats. Experiments were performed in conscious rats given either 20% ethanol or water. In rats submitted to daily ethanol consumption for 13 months, the intragastric injection of 2 g/kg 20% ethanol considerably increased the pancreatic secretion of protein and, to a lesser extent, of water. In control non-alcoholic rats, a short period of increased secretion is followed by a major inhibition of pancreatic secretion, this reverse reaction to ethanol of pancreatic secretion according to whether or not rats are adapted to regular ethanol consumption is similar to what has been previously observed in dog. In chronic alcoholic rats, the release of secretin is probably not very different from controls.