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D W Rattner

Publications and source records attributed to D W Rattner.

At least 73 records · Page 4Linked to original sources
PubMed1995

Increased intrapancreatic trypsinogen activation in ischemia-induced experimental pancreatitis.

OBJECTIVE: The potential of pancreatic ischemia to cause acute pancreatitis as indicated by morphologic changes and ectopic trypsinogen activation was investigated. BACKGROUND: Experimental evidence has shown that pancreatic ischemia is important in the evolution of severe pancreatitis, but whether ischemia can initiate pancreatitis has been disputed. METHODS: Pancreatic ischemia was induced in rats by hemorrhagic hypotension (30 mm Hg for 30 min; n = 64). Changes of pancreatic microcirculatory perfusion were studied using diffuse reflectance spectroscopy. Serum amylase, trypsinogen activation peptide (TAP) in serum and pancreatic tissue, wet/dry weight ratio, and histology were determined over 24 hours and compared with sham-operated control subjects (n = 35). RESULTS: In control animals, serum amylase (47.9 +/- 2.1 units/L), serum (7.9 +/- 0.7 nmol/L) and tissue TAP (63.0 +/- 5.4 nmol/L x g), wet/dry weight ratio (2.8 +/- 0.1), and histology remained unchanged. Temporary hypotension markedly decreased pancreatic perfusion with incomplete recovery after reperfusion. Pancreatic isoamylase activity increased within 1 hour (110 +/- 5 units/L, p < 0.05) and further to 151 +/- 18 units/L at 24 hours. Tissue TAP was elevated at 1 hour (134 +/- 16 nmol/L x g, p < 0.05) and increased to 341 +/- 43 nmol/L x g (p < 0.001) after 24 hours, whereas serum TAP remained unchanged (8.3 +/- 0.5 nmol/L). Morphologic alterations included elevated wet/dry weight ratio (4.1 +/- 0.3, p < 0.01) and increased histologic scores for edema (p < 0.05) and acinar necrosis (p < 0.05) at 24 hours. Trypsinogen activation preceded the development of pancreatic necrosis. CONCLUSIONS: In addition to its potentiating role, severe pancreatic ischemia can play a pathogenetic role in the initiation of acute pancreatitis.

Amylases↗
PubMed1995

Pathogenesis and prevention of early pancreatic infection in experimental acute necrotizing pancreatitis.

OBJECTIVE: The authors test antibiotic strategies aimed at either mitigating bacterial translocation from the gut or delivering antibiotics specifically concentrated by the pancreas for prevention of early secondary infection after acute necrotizing pancreatitis. BACKGROUND: Infection currently is the principal cause of death after severe pancreatitis. The authors have shown that the risk of bacterial infection correlates directly with the degree of tissue injury in a rodent model of pancreatitis. Bacteria most likely arrive by translocation from the colon. METHODS: Severe acute necrotizing pancreatitis was induced in rats by a combination of low-dose controlled intraductal infusion of glycodeoxycholic acid superimposed on intravenous cerulein hyperstimulation. At 6 hours, animals were randomly allocated to five treatment groups: controls, selective gut decontamination (oral antibiotics and cefotaxime), oral antibiotics alone, cefotaxime alone, or imipenem. At 96 hours, surviving animals were killed for quantitative bacterial study of the cecum, pancreas, and kidney. RESULTS: The 96-hour mortality (35%) was unaffected by any treatment regimen. Cecal gram-negative bacteria were significantly reduced only by the oral antibiotics. Pancreatic infection was significantly reduced by full-gut decontamination and by imipenem, but not by oral antibiotics or by cefotaxime alone. Renal infection was reduced by both intravenous antibiotics. CONCLUSIONS: Early pancreatic infection after acute necrotizing pancreatitis can be reduced with a full-gut decontamination regimen or with an antibiotic concentrated by the pancreas (imipenem) but not by unconcentrated antibiotics of similar spectrum (cefotaxime) or by oral antibiotics alone. These findings suggest that 1) both direct bacterial translocation from the gut and hematogenous seeding interplay in pancreatic infection while hematogenous seeding is dominant at extrapancreatic sites and 2) imipenem may be useful in clinical pancreatitis.

Acute Disease↗
PubMed1995

Late histopathologic changes and healing in an improved rodent model of acute necrotizing pancreatitis.

Studies of experimental pancreatitis have generally focussed on early time points rather than the stages of healing and resolution or scarring. We recently characterized a new pancreatitis model of moderate severity by combining intraductal infusion of very low concentrations of glycodeoxycholic acid with intravenous caerulein. This study evaluates late histopathologic changes and gross complications in this pancreatitis model compared to the traditionally used high-dose bile salt model in rats. After 14 days, histopathologic features of caerulein pancreatitis were not different from saline controls. High-dose intraductal bile salt infusion resulted in widespread chronic inflammation, acinar dilation and atrophy, marked reactive stromal proliferation, and ductular budding with periductal fibrosis. In contrast, animals receiving low-dose intraductal bile salt infusion combined with intravenous caerulein demonstrated a moderate degree of chronic inflammation and acinar atrophy along with an intermediate degree of periductal fibrosis and stromal reaction. We conclude that due to its moderate degree of injury, this model may be useful for the study of tissue injury and repair following acute pancreatitis.

Acute Disease↗
PubMed1995

Initial experience with laparoscopic Nissen fundoplication.

In an effort to explore the utility of classic Nissen fundoplication performed laparoscopically, 16 adult patients with well documented gastroesophageal reflux underwent laparoscopic Nissen fundoplication. A full gastric fundal dissection was performed, with division of at least 2 short gastric vessels. The crura were approximated with 1-3 sutures, and a loose fundoplication was performed over an esophageal dilator (minimum 46 F) with three stitches, encompassing the esophageal wall (2.5 cm in length). All patients had symptoms of reflux refractory to medical therapy, and four had an esophageal stricture requiring preoperative dilatation. Fifteen of 16 procedures were completed laparoscopically; one patient required conversion to an open procedure to control bleeding from a posterior gastric vein. There were no other operative complications. The average operative time was 180 minutes (range 120-285). Clear liquids were begun at the passage of flatus (average 2.7 days postop), and patients were discharged an average of 4.1 days postoperatively. Postoperative complications included ileus (1 patient for 6 days), severe subcutaneous emphysema (1 patient), and dysphagia requiring dilatation (5 patients). In short follow-up (mean 4.43 mo., range 1-12 mo.) 14 of 15 patients had complete abolition of reflux symptoms, but one patient with persistent heartburn had reflux demonstrated on a postoperative upper GI series. Thirteen of 16 patients returned to full function within 14 days of surgery. We conclude that standard Nissen fundoplication is possible laparoscopically, and allows a rapid recovery from surgery. However, it is difficult, time consuming, and associated with a significant rate of recurrence in the short term (6%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Failure of symptomatic relief after pancreaticojejunal decompression for chronic pancreatitis. Strategies for salvage.

OBJECTIVE: To evaluate causes of intractable recurrent pain following pancreaticojejunostomy for chronic pancreatitis and to evaluate treatment strategies aimed at lasting pain relief. DESIGN: Case series. SETTING: Tertiary care referral center. PATIENTS: Fifteen selected patients having severe pain associated with chronic pancreatitis with onset 0 to 60 months (median, 5 months) following pancreaticojejunostomy. Each patient underwent computed tomography and endoscopic retrograde cholangiopancreatography. Two patients (13%) were found to have pancreatic cancer, two (13%) had inadequate pancreatic duct decompression, two (13%) had biliary stenosis, and 10 (67%) had presumed neuropathy in the pancreatic head. INTERVENTIONS: Fourteen (93%) of the 15 patients underwent the following reoperations: distal pancreatectomy and splenectomy (one patient), extension of the pancreaticojejunostomy and choledochojejunostomy (one patient), biliary stenting followed by choledochojejunostomy (one patient), and Whipple-type resection of the pancreatic head (14 patients). Two patients subsequently underwent a completion pancreatectomy. MAIN OUTCOME MEASURES: Pain relief, functional capacity, and pancreatic exocrine and endocrine status were determined. The median follow-up after reoperation was 39 months. RESULTS: Of the 14 patients who underwent reoperation, 13 were long-term survivors. One died of pancreatic cancer. Ten of the other 13 have had satisfactory-to-excellent relief of pain, with resumption of a normal level of function. Of the 10 previously euglycemic patients who underwent pancreatic head resection, eight remain free of diabetes mellitus to date. CONCLUSIONS: The causes of recurrent or persistent pain following pancreaticojejunal decompression for chronic pancreatitis are complex and include neuropathic changes, residual or evolving pancreatic and biliary duct obstruction, and unrecognized pancreatic cancer. Acceptable outcomes can usually be achieved by following a treatment strategy aimed at addressing identified residual disease while maximally preserving pancreatic tissue.

Adult↗
PubMed1994

Intravenous contrast medium impairs oxygenation of the pancreas in acute necrotizing pancreatitis in the rat.

OBJECTIVE: Contrast-enhanced computed tomography is widely used to evaluate severe acute necrotizing pancreatitis (ANP) by demonstrating areas of malperfusion, which might indicate irreversible necrosis. Because of our prior finding that the intravenous contrast medium (CM) accentuates the severity of ANP by promoting further necrosis and higher mortality, we sought to investigate the mechanism by which this injury is mediated. DESIGN: Mild acute pancreatitis was induced in Sprague-Dawley rats with intravenous caerulein hyperstimulation; and severe ANP, with intravenous caerulein plus intraductal glycodeoxycholic acid. Control animals and rats with pancreatitis were randomized to be given intravenous CM or saline. MAIN OUTCOME MEASURE: Diffuse reflectance spectroscopy was used to measure the index of hemoglobin content and oxygen saturation in pancreatic tissues in vivo. RESULTS: Oxygen saturation of hemoglobin was increased in animals with mild acute pancreatitis (AP) (mean [+/- SEM], 58.7% +/- 1.2% vs 55.2% +/- 1.5% in control animals; P < .05) and was decreased in animals with ANP (51.2% +/- 1.2% vs 55.2% +/- 1.5%; P < .05). Fifteen minutes after the infusion of CM, oxygen saturation of hemoglobin significantly decreased further in animals with ANP (51.4% +/- 1.8% before infusion of CM vs 46.1% +/- 1.7% at 15 minutes; P < .05) and remained significantly below the comparable group receiving intravenous saline for the entire 60-minute test. This decrement was not observed in animals with ANP given saline or in animals with mild AP or in control animals after infusion of saline or CM. The index of hemoglobin content remained unchanged throughout the experiment in all groups. CONCLUSIONS: The prolonged reduction of oxygen saturation of hemoglobin in the pancreas following the administration of intravenous CM in rats with severe ANP indicates that CM impairs the pancreatic microcirculation in necrotizing forms of AP. This may explain our previous finding that CM increases pancreatic injury and mortality in rodents with ANP, and it underlines our concern that the use of contrast-enhanced computed tomography early in human AP may promote the evolution of pancreatic necrosis.

Acute Disease↗
PubMed1994

Exocrine hyperstimulation but not pancreatic duct obstruction increases the susceptibility to alcohol-related pancreatic injury.

OBJECTIVE: To evaluate the factors thought to be involved in the pathogenesis of acute pancreatitis associated with alcohol. BACKGROUND: The mechanism of alcohol-induced pancreatitis is believed to involve synergistic effects of various pathogenetic factors. The present study was designed to evaluate the possible contribution of pancreatic duct obstruction, physiologic exocrine stimulation, or secretory hyperstimulation to alcohol-induced pancreatic injury. METHODS: Wistar rats were allocated randomly to a control group (group 1), or to a group with pancreatic duct obstruction (group 2), physiologic exocrine stimulation (group 3), ductal obstruction and exocrine stimulation (group 4), or exocrine hyperstimulation with the cholecystokinin analogue cerulein (group 5). Three hours after this pretreatment, animals in each experimental group were randomly divided into two subgroups for intragastric administration of either water (groups 1A through 5A) or beer (groups 1B through 5B). Test solutions were instilled over 9 hours (total amount of alcohol administered, 4.8 g/kg). Twenty-four hours after beginning the test infusion, animals were killed for histologic evaluation of pancreatic edema and determination of an acinar cell necrosis score. Serum amylase levels were determined at 3, 9, and 24 hours. RESULTS: No increase in amylase levels or significant morphologic changes were found in control animals (group 1A) or in animals subjected to physiologic exocrine stimulation (group 2A). Pancreatic duct obstruction, with or without physiologic exocrine hyperstimulation (groups 3A and 4A), and exocrine hyperstimulation (group 5A) induced pancreatitis of similar severity with minor acinar cell damage. Alcohol superimposed on exocrine hyperstimulation (group 5B) increased acinar cell injury (group 5A, 0.4 +/- 0.1 points vs 5B, 1.0 +/- 0.2 points; P < .05) and serum amylase levels at 24 hours (group 5a, 41 +/- 6 U/L vs group 5B, 72 +/- 11 U/L; P < .05), whereas no differences between subgroups A and B (water vs beer) were found in groups 1 through 4. CONCLUSION: Our findings suggest that the pathogenesis of acute alcoholic pancreatitis may require a state of exocrine hyperstimulation, perhaps via cholecystokinin, but do not support a role for constriction or obstruction of Oddi's sphincter.

Acute Disease↗
PubMed1994

A rat model to study hypercalcemia-induced acute pancreatitis.

Hypercalcemia causes acute pancreatitis in humans, a phenomenon reproduced experimentally in cats and guinea pigs. Because the rat is the most frequently used animal for the study of experimental pancreatitis, the present studies were performed to evaluate the effects of hypercalcemia in the rat. In in vitro studies, pancreatic lobules were prepared from fasted Wistar rats (200-250 g) and incubated in HEPES bicarbonate-buffered medium (pH 7.4) containing 0, 0.6, 1.2, 2.5, 5, and 10 mM CaCl2 with or without carbachol 10(-6) M. Amylase was measured in the medium after 30 min to 3 h, and expressed as percent of total amylase. In in vivo studies, fasted male Wistar rats (300-400 g) received calcium (CaCl2; 0.6 mmol/kgh) into the tail vein for 12 h. Control animals received NaCl 0.9% infusion. Histologic slides (H&E-stained) were evaluated in a blinded fashion. Pancreatic lobules showed a higher basal amylase output when incubated in higher calcium medium. The largest, significant difference (2.6-fold) was between 0.6 and 5 mM medium CaCl2 (p < 0.05). Carbachol-stimulated amylase release was again higher with increasing medium calcium with the most pronounced difference (1.3-fold) between 0.6 and 2.5 mM CaCl2 (p < 0.05). In vivo calcium-treated animals showed accumulation of zymogen granules in the cytoplasm, cytoplasmic vacuolization, focal acinar cell depolarization, acinar necrosis, and edema. Calcium causes amylase release from rat pancreatic lobules in vitro. Higher medium calcium levels both significantly increase amylase release from unstimulated and carbachol stimulated lobules. Twelve-hour in vivo calcium infusion leads to accumulation of zymogen granules in acinar cells and acinar injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Intravenous contrast medium accentuates the severity of acute necrotizing pancreatitis in the rat.

BACKGROUND/AIMS: Contrast-enhanced computed tomography (CECT) is used to show areas of decreased pancreatic perfusion in severe acute pancreatitis (AP). To evaluate possible adverse effects of the contrast medium (CM) on the course of AP, the impact of intravenous CM in AP of graded severity in the rat was studied. METHODS: Pancreatitis of three levels of severity was induced in Sprague-Dawley rats with intravenous cerulein hyperstimulation plus time- and pressure-controlled intraductal infusion of saline or glycodeoxycholic acid. At 7 hours, control and pancreatitis animals received intravenous ionic CM, nonionic CM, or saline. The principal outcome measures were 24-hour survival, trypsinogen activation peptides (TAP) in ascites, and histological acinar necrosis score. RESULTS: There was no measurable effect of CM on the index features in control animals or animals with mild or moderate AP. In severe AP, CM caused a significant increase in mortality, ascites TAP, and necrosis score. CONCLUSIONS: Intravenous CM increases pancreatic injury when administered early in the course of severe experimental AP. Because CM may convert borderline ischemia to irreversible necrosis, CECT performed early in pancreatitis to show poor perfusion and predict areas of necrosis may depict a self-fulfilling prophecy. Early CECT should be reconsidered and perhaps avoided.

Acute Disease↗
PubMed1994

Time course of bacterial infection of the pancreas and its relation to disease severity in a rodent model of acute necrotizing pancreatitis.

BACKGROUND: Bacterial infection of pancreatic necrosis is thought to be a major determinant of outcome in acute necrotizing pancreatitis. The determinants and possibilities for prophylaxis are unknown and difficult to study in humans. OBJECTIVE: The time course of bacterial infection of the pancreas in a rodent model of acute necrotizing pancreatitis was characterized. The authors ascertained if there is a correlation with the degree of necrosis. METHODS: Acute pancreatitis (AP) of graded severity was induced under sterile conditions by an intravenous infusion of cerulein (5 micrograms/kg/hr) for 6 hours (mild AP), or a combination of intravenous cerulein with an intraductal infusion of 10-mM glycodeoxycholic acid (0.2 mL for 2 min for moderate AP, 0.5 mL for 10 min for severe AP). Sham-operated animals (intravenous and intraductal NaCl 0.9%) served as controls. Ninety-six hours after induction, animals were killed for quantitative bacterial examination and histologic scoring of necrosis. In addition, groups of animals with severe AP were investigated at 12, 24, 48, 96, and 144 hours. RESULTS: No significant pancreatic necrosis was found in control animals (0.3 +/- 0.1) or animals with mild AP (0.6 +/- 0.1) killed at 96 hours. Necrosis scores were 1.1 +/- 0.2 for animals with moderate AP and 1.9 +/- 0.2 for animals with severe AP. Control animals did not develop significant bacterial infection of the pancreas (> or = 10(3) CFU/g). At 96 hours, the prevalence of infection was 37.5% in animals with mild AP and 50% in animals with moderate AP. In animals with severe AP, infection of the pancreas increased from 33% in the first 24 hours to 75% between 48 and 96 hours (p < 0.05). The bacterial counts and the number of different species increased with time and was maximal (> 10(11) CFU/g) at 96 hours. CONCLUSION: Bacterial infection of the pancreas in rodent AP increases during the first several days, and its likelihood correlates with the severity of the disease. This model, which closely mimics the features of human acute pancreatitis, provides a unique opportunity to study the pathogenesis of infected necrosis and test therapeutic strategies.

Acute Disease↗
PubMed1994

Pancreatic microcirculatory changes in experimental pancreatitis of graded severity in the rat.

BACKGROUND: A technique with two complementary methods, intravital microscopy (IVM) and diffuse reflectance spectroscopy (DRS), was developed to analyze pancreatic tissue perfusion. METHODS: After initial in vivo and in vitro validation of the techniques, we studied pancreatic microcirculation in models of mild, moderate, and severe pancreatitis. Anesthetized Sprague-Dawley rats were randomly allocated to the three models or to serve as controls. Stable systemic hemodynamic parameters were maintained with normal saline solution infusion. Exocrine capillary perfusion was assessed by IVM; hemoglobin oxygenation and hemoglobin content were measured by DRS. RESULTS: Capillary perfusion in mild pancreatitis initially increased significantly at 30 minutes to 155% +/- 38% of baseline values but returned to baseline within 3 hours. Hemoglobin content and oxygen saturation remained stable. In moderate and severe pancreatitis capillary perfusion significantly decreased versus the control group to 12% +/- 6% and 6% (range, 0% to 14%) of baseline values, respectively, at 6 hours. Oxygen saturation decreased significantly in moderate pancreatitis from 48.5% +/- 2.3% to 41.6% +/- 3.5% (p < 0.05) and in severe pancreatitis from 47.2% +/- 1.5% to 38.9% +/- 0.5% (p < 0.05), whereas hemoglobin content did not change. CONCLUSIONS: We conclude that (1) IVM and DRS provide both unique and complementary data on tissue perfusion of the pancreas, (2) that moderate and severe experimental pancreatitis are accompanied by progressive tissue ischemia, and (3) that significant stasis (decreased perfusion) and decreased oxygen saturation occur whereas generalized vasoconstriction (decreased hemoglobin levels) was not found. In contrast, mild experimental pancreatitis was accompanied by initial hyperperfusion and normal oxygen delivery was maintained.

Animals↗
PubMed1994

Failure of pentoxifylline to ameliorate severe acute pancreatitis in the rat: results of a prospective, randomized, controlled study.

OBJECTIVE: To investigate the benefit of pentoxifylline in severe experimental pancreatitis. DESIGN: Prospective, randomized, controlled study. SETTING: Experimental animal laboratory in a University hospital. SUBJECTS: Forty-two adult male Sprague-Dawley rats. INTERVENTIONS: Acute pancreatitis was induced by supramaximal stimulation with cerulein plus a pressure and volume controlled 10 min intraductal infusion of 10-mM glycodeoxycholic acid. Thirty minutes after pancreatitis was induced, animals were randomized to receive pentoxifylline (60 mg/kg over 2.5 hrs), or saline. All animals received fluid resuscitation with lactated Ringer's solution (8 mL/kg/hr), and surviving animals were killed at 24 hrs. MEASUREMENTS AND MAIN RESULTS: There was a progressively significant decrease in mean arterial pressure after pancreatitis was induced, with no difference between pentoxifylline-treated rats and controls. Hematocrit increased significantly in both groups at 6 hrs, and returned to baseline values at 24 hrs. Ascites volume and levels of trypsinogen activation peptide in plasma and ascites were similar in both groups. Twenty-four hour mortality was 47% for the pentoxifylline group and 52% for the control group. Histologic scores for necrosis, edema, inflammation, and hemorrhage showed no significant differences between the two groups. CONCLUSION: Treatment with pentoxifylline failed to improve outcome in a model of severe acute pancreatitis in the rat.

Acute Disease↗
PubMed1994

Impairment of pancreatic microcirculation correlates with the severity of acute experimental pancreatitis.

BACKGROUND: Altered microcirculatory perfusion may be an important factor in the pathogenesis of necrotizing pancreatitis. Diffuse reflectance spectroscopy (DRS) can measure dynamic alterations in the microcirculation over a larger area than intravital microscopy. STUDY DESIGN: We used DRS to characterize changes in the microcirculation during the evolution of pancreatitis of varying severity. Male Sprague Dawley rats (330 to 400 g) were randomly allocated to four groups: control (n = 18), mild pancreatitis (n = 18), moderate pancreatitis (n = 18), or severe pancreatitis (n = 34). Within each group, rats were studied 0.5, 3.0, or 6.0 hours after induction of pancreatitis to determine total hemoglobin content (IHb) and hemoglobin oxygenation (ISO2). RESULTS: Total hemoglobin content in the pancreas remained constant in all groups. Hemoglobin oxygenation increased significantly in rats in the control group and in rats with mild pancreatitis for the duration of the experiment, but not in rats with moderate or severe pancreatitis. Rats with severe pancreatitis had a significant decrease in ISO2 six hours after the induction of pancreatitis compared with baseline values (49.18 +/- 1.55 versus 52.01 +/- 0.19, p < 0.01) as well as rats in the control group that were studied after six hours (49.18 +/- 1.55 versus 55.92 +/- 1.07, p < 0.02). Furthermore, there was marked variability in IHb and ISO2 at different locations within the same pancreas in rats with severe pancreatitis, which was not observed in the control group or in the rats with mild or moderate pancreatitis. CONCLUSIONS: Impaired microcirculatory perfusion characterizes severe, but not mild, pancreatitis. The predominant early change is stasis rather than vasoconstriction. As the changes become more severe, necrosis occurs in a heterogeneous distribution.

Acute Disease↗
PubMed1994

Interstitial protease activation is the central event in progression to necrotizing pancreatitis.

BACKGROUND: Although intracellular protease activation is thought to be an early event in acute pancreatitis, factors determining progression from edematous to necrotizing pancreatitis are largely unknown. With enterokinase as a probe and an immunoassay quantifying free trypsinogen activation peptides (TAP), we sought evidence for the presence of interstitial trypsinogen in edematous pancreatitis and documented the effects of its ectopic activation. METHODS: Edematous pancreatitis in the rat was induced by supramaximal stimulation with cerulein (5 micrograms/kg/hr) and coupled with enterokinase infused into the pancreatic duct at 30 mm Hg. Blue dextran infusion at this pressure corroborated interstitial delivery. Rats with no stimulation, maximal physiologic stimulation (0.25 microgram/kg/hr of cerulein), or intraductal saline infusion served as controls. TAP levels measured by enzyme-linked immunosorbent assay, 6-hour survival, and histopathology were used as end points. RESULTS: Intraductal enterokinase infusion alone or in combination with maximal physiologic stimulation generated only slight increases in TAP level and no or minimal pancreatic injury. In contrast, enterokinase superimposed on edematous pancreatitis (supramaximal cerulein stimulation) produced fulminant pancreatitis and rapid death of all animals within 6 hours. Pancreatic histopathology showed severe intrapancreatic hemorrhage, acinar inflammation, and necrosis. TAP levels were significantly higher in plasma (p = 0.02), urine (p = 0.05), and ascites (p < 0.001) when compared with all other groups. CONCLUSIONS: In edematous pancreatitis a large pool of trypsinogen accumulates in the interstitial space. Activation of these proenzymes leads to catastrophic consequences and may underlie progression from mild to necrotizing pancreatitis.

Animals↗
PubMed1994

[Trypsinogen activation peptides in acute pancreatitis. Experimental data and clinical implications].

Trypsinogen activation peptides (TAP) can be found in patients with acute pancreatitis (AP) as well as in different models of experimental AP. First experience has suggested that early elevation of TAP indicates development of necrotizing AP and that the amount of TAP correlates with the extent of acinar cell necrosis and mortality. It is however unknown whether TAP similarly assess severity of AP in the later course of the disease. The present study monitores TAP in plasma, urine and ascites during the initial development of pancreatic injury and correlates the amount of TAP and the extent of pancreatic necrosis over 48 h in a rodent model of AP. While there was no elevation of TAP in control animals or animals with edemantous AP, significant amounts of TAP im plasma were found as early as 30 min following induction of severe necrotizing AP. Serum amylase returned to normal values within 24 h, TAP maintained at high levels until the end of the 48 h observation period. During the first 24 h TAP paralleled the development of acinar cell necrosis, but decreased thereafter despite further progression of pancreatic injury. Our results provide further evidence suggesting that TAP initially precede morphological changes in AP. Early in the course of the disease TAP parallel development of pancreatic injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Evidence for extraluminal trypsinogen activation in three different models of acute pancreatitis.

BACKGROUND: Inappropriate extraluminal activation of trypsin is assumed to play a part in the pathogenesis of acute pancreatitis (AP), but proof has been elusive because active trypsin is transient and difficult to measure. We have previously shown increased levels of trypsinogen activation peptides (TAP), a direct measure of trypsin activation, to correlate with severity of AP, tissue necrosis, and survival in a rodent model induced by cerulein hyperstimulation and bile salt infusion. The present study seeks to show that increased trypsinogen activation also characterizes three other models of experimental AP in rodents to give credence to the generality of the phenomenon and to its potential relevance to human AP. METHODS: Experimental AP was induced in mice by a choline-deficient diet supplemented with ethionine and in rats by creation of a closed duodenal loop or by ligation of the biliopancreatic duct plus physiologic stimulation. TAP were quantified by an immunoassay in tissue and plasma at various time points after onset of AP. RESULTS: In the group with choline-deficient diet supplemented with ethionine a significant increase in tissue and plasma TAP was found at 48 and 72 hours, respectively. In the group with closed duodenal loop significant TAP elevations were found in plasma as early as 6 hours and in the group with ligation of the biliopancreatic duct plus physiologic stimulation at 24 hours. CONCLUSIONS: These experiments provide further evidence that extraluminal protease activation is a pathophysiologic event common to the evolution of various models of experimental acute pancreatitis and therefore increase the likelihood that this phenomenon is important in the human disease as well.

Acute Disease↗