Pancreatic Morphological Changes Research Articles

Managements of painless chronic pancreatitis

Objective To explore the treatments and their effects on painless chronic pancreatitis （CP） in adult. Methods A historical cohort study of adult subjects with CP, who were hospitalized in our center in the last decade, was performed, and the clinical data were analyzed. Results There were 56 cases of adult painless CP, and 46（82. 1% ） （31 males and 15 females, age 51.6 ± 14. 5 years） were followed up（34. 5 ± 27.1 months）. Imaging findings showed 26 cases of pancreatic duct stones and morphological changes. These patients received endoscopic intervention therapy （ n = 14 ） , surgical procedures （ n = 7 ） , combined endoscopic and surgical treatment （ n = 3 ） and conservative treatment （ n = 2 ）. Another group of 18 cases of pancreatic or peripheral occupying lesions received surgery. During follow-up of the above 2 groups, 1 patient died of pancreatic cancer in each group. The symptoms of diabetes and diarrhea were not relieved, but there was improvement of general condition in some patients. Stones re-occurred after surgery in one patient. Two patients with pancreatic duct dilation and cysts underwent endoscopic treatment（ n = 1 ） and surgical procedure（ n = 1 ） , respectively. But the latter patient experienced gastric bleeding, cirrhosis and jaundice with unknown reason after the surgery. Conclusion In adult patients with CP, endoscopic and surgical procedures had similar effect in patients with pancreatic duct stones and dilation. Surgical procedures are preferably performed in those with pancreatic occupying lesions. Further study is needed in those only with pancreatic duct dilation. The above treatments can improve general conditions in some patients. Intensive surveillance is suggested to the patients with painless CP. Key words: Pancreatitis, chronic ; Painless ; Cholangiopancreatography, endoscopic retrograde ; Surgical procedures; Treatment effectiveness

Pancreatic Damage after the First Episode of Acute Alcoholic Pancreatitis and Its Association with the Later Recurrence Rate

Background: Acute alcoholic pancreatitis (AAP) recurs in up to half of the patients, continuous alcohol consumption being an important risk factor. Changes in pancreatic function and morphology after acute pancreatitis have been characterized previously, but their association with later recurrences has not been adequately studied. Patients and Methods: In this prospective follow-up study, the pancreatic function of 54 patients (47 males and 7 females) with a median age of 49 years (range 25–71) and morphology (35 patients) were evaluated. Pancreatic morphology was evaluated by secretin-stimulatedmagneticresonancepancreatography (SMRP). Patients were evaluated early (baseline) and at 2 years after the first episode of AAP. In order to evaluate later recurrences, the patients were followed for a median of 47 (range 28–66) months. Results: Of the 46 patients without previous diabetes, 17 patients (37%) developed impaired glucose metabolism during the 2 years following the first AAP. The prevalence of exocrine dysfunction decreased from 39% at baseline to 9% at 2 years. Of the patients with severe pancreatitis (n = 13, 24%), 31% had elevated glycosylated haemoglobin levels compared to 7% in patients with mild pancreatitis [p = 0.05, odds ratio (OR): 5.5, 95% confidence interval (CI): 1.04-29.0]. Twenty percent (7/35) of the patients had changes consistent with chronic pancreatitis on baseline SMRP, which persisted in all cases. Of the 29% patients with acute changes on baseline SMRP, the acute changes resolved in 50% and chronic pancreatitis was detected in the remaining 50% at 2 years. Development of chronic changes did not depend on continued alcohol consumption, as it was also found in 3 patients practising complete abstinence following their first attack of AAP. The presence of a chronic pseu-docyst at 2 years predicted pancreatitis when compared to patients lacking pseudocyst formation: 4 (80%) versus 5 (17%) (p = 0.01, OR: 20.0, 95% CI: 1.83-219). Conclusion: The severity of the first episode of AAP was associated with deteriorated diabetes control, but not with pancreatic exocrine dysfunction at 2 years. The number of patients with chronic changes on SMRP increased independently of alcohol consumption. Chronic pseudocyst formation seen on SMRP 2 years after AAP was significantly associated with recurrence of pancreatitis.

The tumour-suppressor p53 is not required for pancreatic beta cell death during diabetes and upon irradiation.

Immune-independent diabetes often occurs via pancreatic beta cell dysfunction. However, the role of the tumour suppressor p53 that regulates cellular life and death in multiple tissues, in pancreatic cell death and diabetes has not been clarified. We have therefore utilized an established mouse model for diabetes in which the MHC class I antigen is overexpressed in pancreatic beta cells under the rat insulin promoter, to investigate the role of p53. We show that pancreatic beta cell death, as determined by TUNEL staining, is elevated in transgenic mice compared to wild-type mice. However, there was no increase in immuno-reactivity towards anti-p53 antibodies in the pancreas of transgenic mice over the course of diabetes formation and beta cell death, suggesting that p53 may not be involved in these processes. Interestingly, p53 expression was also not induced in pancreas upon gamma-irradiation, which resulted in a massive increase in the number of TUNEL-positive cells, suggesting that the p53 pathway may not be causally involved in pancreatic cell death. To further confirm these findings, we generated MHC class I transgenic mice lacking p53 expression. Absence of p53 did not result in any significant changes in pancreatic morphology or affect cell death levels. Importantly, p53 absence did not rescue the diabetic phenotype of the transgenic mice. The results therefore demonstrate that p53 may not be causally involved in pancreatic beta cell death, and suggests that the classical cell death pathway dependent on p53 may not be operating in pancreatic beta cells.

Risk factors for recurrent acute alcohol-associated pancreatitis: A prospective analysis

Objective. In an earlier retrospective study we showed that 46% of patients with acute alcoholic pancreatitis had recurrent attacks within 10–20 years, about 30% having a recurrence during the first 3 years. The aim of this prospective follow-up study was to determine the risk factors associated with recurrences. Material and methods. Sixty-eight patients, (59 M, 9 F, mean age 46 years, range 25–71 years) who survived their first acute alcohol-induced pancreatitis from January 2001 to January 2004 volunteered to participate in the study. The diagnostic criteria for acute pancreatitis were epigastric pain, serum amylase >3 times the upper normal range, elevated serum C-reactive protein (CRP), and signs of acute pancreatitis in imaging. Other etiologies were excluded. Alcohol consumption and dependency were detected by the Alcohol Use Disorders Identification Test (AUDIT) and the Short Alcohol Dependence Data (SADD), respectively, and by attempting to evaluate recent use in grams of pure alcohol. Social and demographic data of the patients, smoking, body mass index, and the severity of the pancreatitis were recorded. Serum and fecal markers of the endocrine and exocrine function and secretin-stimulated MRCP were studied. The patients were followed for a median 38 (25–61) months for recurrences, and at the 2-year time-point had a follow-up visit to investigate any changes in alcohol consumption. Results. Seventeen (25%) patients had recurrences of acute alcoholic pancreatitis during the follow-up. Pre-illness alcohol consumption, the severity of the pancreatitis, patient's social or demographic data, pancreatic function tests or morphologic changes in MRCP, or smoking did not correlate with recurrence. None of the 13 patients with consistent total abstinence from alcohol at 2 years developed recurrent pancreatitis compared with 17 out of 51 (33%) patients with at least some alcohol consumption (p=0.02). Use of other sedatives than alcohol before the first attack of pancreatitis was an independent risk factor associated with recurrence (HR = 6.95, 95% CI 2.45–19.72, p<0.001). A lower reduction in dependency on alcohol (less decreased SADD points) during 2 years was associated with a higher recurrence rate (HR = 0.921/each reduced point, 95% CI 0.872–0.974, p=0.004). Conclusions. Contrary to chronic pancreatitis, smoking was not found to be a risk factor for recurrent episodes after the first attack of acute alcoholic pancreatitis. Abstinence from alcohol protects against recurrent pancreatitis. Patients who developed recurrent acute pancreatitis had increased dependency on alcohol, demonstrated by the use of other sedatives in addition to alcohol and supported by the less decreased dependency during the follow-up.

Bile and pancreatic juice exclusion activates acinar stress kinases and exacerbates gallstone pancreatitis

Bile and pancreatic juice exclusion from gut activates acinar stress kinases and exacerbates gallstone pancreatitis as evidenced by the ameliorating effects of replacement therapy in an experimental model of duct ligation-induced acute pancreatitis. In the early stages of gallstone pancreatitis, bile-pancreatic juice cannot enter the gut. Enteral exclusion worsens pancreatitis by causing feedback hyperstimulation of the exocrine pancreas that activates acinar cell stress kinases. Investigations using a unique surgical model, the Donor Rat Model, showed that duodenal replacement of bile-pancreatic juice in rats with duct ligation attenuates pancreatic stress kinase activation, reduces pancreatic cytokine production, and ameliorates pancreatic morphologic changes. These findings suggest that exclusion-induced acinar hyperstimulation, in the presence of duct obstruction, exacerbates acute pancreatitis via stress kinase activation. Although acinar hyperstimulation has often been implicated in the pathogenesis of acute pancreatitis, the lack of supporting evidence remains a conspicuous void. The proposed hypothesis draws on fresh evidence to present a new paradigm that reexamines the role of exocrine pancreatic hyperstimulation in gallstone pancreatitis pathogenesis.

DUCT OBSTRUCTION AND BILE-PANCREATIC JUICE (BPJ) EXCLUSION ARE REQUIRED FOR MAXIMUM PANCREATIC INFLAMMATORY MEDIATOR PRODUCTION IN LIGATION-INDUCED ACUTE PANCREATITIS IN RATS

Bile-pancreatic duct ligation obstructs the duct, excludes BPJ from gut, and induces acute pancreatitis. Using our unique Donor Rat Model, we previously showed that combined duct obstruction and BPJ exclusion is associated with the most severe pancreatic morphologic changes and hypercholecystokininemia when compared to duct obstruction alone or BPJ exclusion alone. Here, we test the hypothesis that combined Obstruction + Exclusion (OE) is associated with greater production of pancreatic inflammatory mediators than either Obstruction alone (O) or Exclusion alone (E). Sham controls had duct dissection only (S). We measured pancreatic production of cytokines (IL-1, IL-12) and chemokines (MCP-1, RANTES) at the 1- and 3-hr time points using ELISA. P < 0.05; ANOVA, n = 6-7 rats/groups. Compared to Sham, OE was associated with marked increases in pancreatic cytokine (IL-1, IL-12) and chemokine (MCP-1, RANTES) production that were significantly ameliorated by enteral BPJ replacement (O vs OE). Although E alone was associated with inflammatory mediator production that was mildly greater than Sham (E vs S), the increase was still significantly below that of rats with duct ligation (E vs OE). In summary, pancreatic cytokine production and chemokine production are markedly greater with combined Obstruction + Exclusion than either Obstruction alone or Exclusion alone (OE vs O or E). These findings indicate that both duct obstruction and BPJ exclusion are essential for the maximum production of acute inflammatory mediators in the pancreas in ligation-induced acute pancreatitis. Our results support our central hypothesis that BPJ exclusion from gut plays an important role in the mechanism of disease pathogenesis. (Support: American College of Surgeons Faculty Research Fellowship 2003-2005; NIH K08 Career Development Award #K08-DK062805)

Exacerbation of acute pancreatitis by combined cholinergic stimulation and duct obstruction

Background The role of cholinergic pathways in the pathogenesis of bile-pancreatic duct ligation (BPDL)-induced acute pancreatitis in rats remains controversial. We hypothesized that cholinergic stimulation exacerbates acute pancreatic inflammation in the presence of duct obstruction. Methods We studied 34 rats divided into 5 groups as follows: (1) sham operation; (2) BPDL; (3) BPDL with duodenal bile-pancreatic juice (BPJ) replacement fresh from a donor rat; (4) BPDL with BPJ replacement as in 3 above, and carbachol (CCh) 5 ug/h subcutaneously; or (5) CCh 5 ug/h subcutaneously only. Rats were killed after 6 hours. Results The P value was less than .05 by analysis of variance. Pancreatic morphologic changes and zymogen fraction hyperamylasemia seen with duct ligation (2 vs. 1) were ameliorated significantly by duodenal BPJ replacement (3 vs. 2), but not when exogenous CCh was administered (4 vs. 3), whereas CCh alone showed no significant changes compared with sham (5 vs. 1). Conclusions Cholinergic stimulation and duct obstruction synergistically amplify acinar hyperstimulation and exacerbate acute pancreatitis.

Bile-pancreatic juice (BPJ) exclusion exacerbates Akt/NF-kB pathway activation and increases chemokine production in ligation-induced acute pancreatitis

Abstract Introduction: Using a unique surgical model (The Donor Rat Model) we showed that duodenal replacement of BPJ, obtained fresh from a Donor Rat, ameliorates pancreatic morphologic changes, hyperamylasemia and hypercholecystokininemia in ligation-induced acute pancreatitis. We hypothesize that BPJ exclusion from gut exacerbates Akt/NF-kB pathway activation and induces proinflammatory chemokine production in ligation-induced acute pancreatitis. The cytosolic IkB/NF-kB complex dissociates when IkB is phosphorylated following Akt activation, allowing NF-kB to translocate to the nucleus and induce transcription of various inflammatory mediators including chemokines. Methods: We studied rats as follows: Diseased-controls had bile-pancreatic duct ligation. Diseased-treated rats had duodenal BPJ replacement fresh from a Donor Rat beginning immediately before duct ligation. Sham controls had ducts dissected only. Rats were killed after 1 or 3 hours (n = 7/group). Pancreatic homogenates were used to determine Akt activation (immunoblotting, immunecomplex kinase assay and ELISA), IkB activation (immunoblotting), and production of chemokines MCP-1 and RANTES (ELISA). NF-kB was quantitated in pancreatic nuclear fractions using EMSA. Results: Compared to sham, duct ligation was associated with marked increases in pancreatic Akt and IkB activation, NF-kB nuclear translocation, and MCP-1 and RANTES production. Akt/NF-kB pathway activation and increased MCP-1 and RANTES production after duct ligation were substantially ameliorated by BPJ replacement (ANOVA, p Conclusions: BPJ exclusion from gut exacerbates Akt/NF-kB pathway activation and increases chemokine production in ligation-induced acute pancreatitis. These findings support our central hypothesis that BPJ exclusion-induced acinar cell hyperstimulation exacerbates acute pancreatic inflammation in this experimental corollary of gallstone-induced acute pancreatitis. (Support: ACS Faculty Research Fellowship, NIH-K08 Award#DK062805)

Overexpression of heat shock protein Hsp27 protects against cerulein-induced pancreatitis

Background & Aims: Heat shock protein (Hsp) 27 regulates actin cytoskeletal dynamics, and overexpression of Hsp27 in fibroblasts protects against stress in a phosphorylation-dependent manner. Induction of Hsps occurs in acute pancreatitis, but Hsp27 has not been ascribed a specific role. To examine whether Hsp27 would ameliorate acute pancreatitis, we generated transgenic mice overexpressing human Hsp27 (huHsp27) or Hsp27 with the phosphorylatable residues Ser 15,78,82 mutated to aspartic acid (huHsp27-3D) to mimic phosphorylation or to alanine (huHsp27-3A), which is nonphosphorylatable. Methods: huHsp27 was expressed at high levels in the exocrine pancreas by use of a cytomegalovirus promoter. Protein expression was analyzed by Western blotting and immunofluorescence. Acute pancreatitis was induced with 6 or 12 hourly cerulein injections (50 μg/kg intraperitoneally) and its severity assessed by measuring serum amylase and lipase levels, pancreatic trypsin activity, edema, and morphologic changes by quantitative scoring of multiple histologic sections and visualization of filamentous actin. Systemic inflammatory effects were monitored by measuring lung myeloperoxidase activity (a marker of neutrophil infiltration). Results: huHsp27 protein was overexpressed in the pancreas and localized to pancreatic acini. Acute pancreatitis was ameliorated by overexpression of huHsp27 and the huHsp27-3D mutant, which were associated with suppression of pancreatic trypsin activity and acinar cell injury and preservation of the actin cytoskeleton. In contrast, these changes were unaffected by overexpression of the nonphosphorylatable huHsp27-3A mutant. Conclusions: Pancreatic overexpression of huHsp27 protects against cerulein-induced acute pancreatitis in a specific phosphorylation-dependent manner and is associated with preservation of the actin cytoskeleton.

Factors associated with health-related quality of life in chronic pancreatitis.

Chronic pancreatitis may lead to considerable reduction in health-related quality of life, but factors associated with a poor perceived health status have not been investigated. We recruited 265 patients with chronic pancreatitis from a tertiary care gastroenterology clinic. Health-related quality of life was assessed using the Short Form-36 Health Survey. Data were compared with age- and gender-adjusted values from the German general population (6964 adults). Factors associated with poor perceived health status were identified by logistic regression. All domains of health-related quality of life were reduced in chronic pancreatitis. Decrements were most pronounced in role limitations caused by physical (-25%) and emotional health problems (-15%), and general health perceptions (-19%). Severity of abdominal pain, chronic pancreatic diarrhea, low body weight, and loss of work independently contributed to the physical component score of the Short Form-36 (adjusted R2= 33.8%) and were the factors most closely associated with poor health status perception. The etiology and duration of the disease or changes in pancreatic morphology had no impact on health-related quality of life. Patients with chronic pancreatitis experience substantial impairments in health-related quality of life. The severity of chronic pancreatitis-related symptoms is directly associated with patient function and well-being. These data offer further insight into the impact of chronic pancreatitis on patient health status and may serve as the basis for the development of disease-specific instruments, which are needed to measure the effect of therapeutic interventions on patient-derived health outcomes.

Effects of short-term chemical ablation of the GIP receptor on insulin secretion, islet morphology and glucose homeostasis in mice

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted by endocrine K-cells in response to nutrient absorption. In this study we have utilized a specific and enzymatically stable GIP receptor antagonist, (Pro3)GIP, to evaluate the contribution of endogenous GIP to insulin secretion and glucose homeostasis in mice. Daily injection of (Pro3)GIP (25 nmol/kg body weight) for 11 days had no effect on food intake or body weight. Non-fasting plasma glucose concentrations were significantly raised (p<0.05) by day 11, while plasma insulin concentrations were not significantly different from saline treated controls. After 11 days, intraperitoneal glucose tolerance was significantly impaired in the (Pro3)GIP treated mice compared to control (p<0.01). Glucose-mediated insulin secretion was not significantly different between the two groups. Insulin sensitivity of 11-day (Pro3)GIP treated mice was slightly impaired 60 min post injection compared with controls. Following a 15 min refeeding period in 18 h fasted mice, food intake was not significantly different in (Pro3)GIP treated mice and controls. However, (Pro3)GIP treated mice displayed significantly elevated plasma glucose levels 30 and 60 min post feeding (p<0.05, in both cases). Postprandial insulin secretion was not significantly different and no changes in pancreatic insulin content or islet morphology were observed in (Pro3)GIP treated mice. The observed biological effects of (Pro3)GIP were reversed following cessation of treatment for 9 days. These data indicate that ablation of GIP signaling causes a readily reversible glucose intolerance without appreciable change of insulin secretion.

Akt-NFkB pathway is activated in duct ligation-induced acute pancreatitis in rats

Bile-pancreatic duct ligation in rats excludes bile-pancreatic juice from gut and induces acute pancreatitis. CCK-A and c:holinergic receptor-mediated exocr/ne pancreatic hyperstimulation secondat 7 to bile-pancreatic juice exclusion ~ implicated in disease pathogenesis. Stimulation of these G protein coupled receptors can activate the Akt-NFkB pathway Nuclear Transcrip~ lion Factor kappa B (NFkB) is a downstream messenger of acinar cell signal transduction via the Akt pathway and is capable o/inr Nag adnar cell cytokina production. We hypothesize that the Akt-NFkB pathway is activated in figation-induced acute pancreatitis. METHODS: We studied rats w~th 1, 3, or 24 hra ot duct ligation or sham-operation (ducts dLssected but not ligated)(n= 5 rats/group). RESULTS: Compared to sham-controls, duct ligation induced acute pancreatitis as evidenced by hyperamylasemia and pancreatic morphologic changes. Electro-mobility shift assay showed a irma-dependent incraase in NFkB in pancreatic nuclear extracts after duct ligation (transcnption factor E-box was used as control; competing cold NFkB prone excluded non-specihc binding), immunobIot analysis of pancreatic homogehates showed mcreases in phospho-Akt and phospho-lkB that were also time-dependent and parallel with NFkB activation (actin immunobiots confirmed equal loadtirg of lanes) (lkB phosphorylation permits translocatinn of NFkB from the cytosol to the nucleus). CONCLUSIONS: 'Paere is a time-dependem and parallel increase in nuclear translocation of NFkB and acuvation of Akt and IkB after duct ligationdnduced acute pancreatitis in rats. These findings are consistent wuh the h)~otbesis that the Akt-NFkB pathway is activated in duct ligation induced acute pancreatitis. In this expemnentaI corollary of gallstone-reduced acute pancreatitts, bile-pancreatic juice exclusion-induced stimulation of acinar cell G protein coupled receptors could exacerbate acute pancreatitis by increased acinar cell production of pro-inflammatory cytokines via lbe Akt-NFkB pathway (Support: Carver Collaborative Pilot Grant; N1H #lK08DK062805)

Suspected early or mild chronic pancreatitis: enhancement patterns on gadolinium chelate dynamic MRI. Magnetic resonance imaging.

To assess whether measuring the pattern of pancreatic enhancement on gadolinium chelate dynamic magnetic resonance imaging (MRI) is helpful for diagnosis of suspected early or mild chronic pancreatitis. In this retrospective study, 24 patients with suspected early or mild chronic pancreatitis, classified by imaging criteria of equivocal chronic pancreatitis (ultrasound, computed tomography [CT] or ERCP) grading, had dynamic MRI that included unenhanced, arterial dominant, early venous, and late venous phases of contrast enhancement. Twenty patients without pancreatic diseases also had the dynamic sequence as a control group. The signal intensity was measured at the pancreatic head, body, and tail on all phases, and for each, the signal intensity ratio (SIR, the signal intensity in postcontrast divided by that in precontrast) was calculated. Two radiologists independently reviewed the images of the patients with suspected early or mild chronic pancreatitis for pancreatic morphologic abnormalities without knowing the results of signal intensity measurements. On unenhanced images, there was no significant difference of signal intensity between control and pancreatitis groups (P < 0.05). In the pancreatitis group, but not in the control group, the unenhanced signal intensity of the pancreatic head and body were significantly higher than that of the tail (P < 0.05). In the control group, the greatest enhancement (highest SIR) after injection was in the arterial phase (1.89 +/- 0.31), significantly higher than that in the early venous phase (1.68 +/- 0.17, P < 0.01) and in the late venous phase (1.61 +/- 0.15, P < 0.001). The pancreatitis group, however, had an arterial phase SIR (1.65 +/- 0.23) that was significantly lower than its early venous phase SIR (1.75 +/- 0.22, P < 0.05) and lower than the arterial phase SIR of the control group (P < 0.01). The presence of an SIR less than 1.73 in the arterial phase and/or a delayed peak enhancement after contrast agent administration had a sensitivity and specificity of diagnosing early or mild chronic pancreatitis of 92% and 75%, respectively. This sensitivity was significantly higher than the sensitivity of 50% for diagnosis based on morphologic abnormalities (P < 0.05). Measuring pancreatic signal intensity on gadolinium chelate dynamic MRI is helpful for diagnosing early or mild chronic pancreatitis, especially before apparent pancreatic morphologic or signal intensity changes are present.

CCK-Stimulated Changes in Pancreatic Acinar Morphology Are Mediated by Rho

Background/Aims: Treatment of isolated pancreatic acini with high concentrations of cholecystokinin (CCK) is known to induce rapid changes in the cellular morphology. The signalling pathways remain to be characterized. Methods: Pancreatic acini were permeabilized by digitonin and incubated with various agents. The acinar morphology was investigated by microscopy. The activation of p125 focal adhesion kinase was determined by Western blot analysis. Amylase was measured photometrically. Results: The functionality of the permeabilized acini was tested by measuring stimulated amylase release. 300 µM GTPγS was almost as efficient as CCK to stimulate amylase release, while 300 µM GDPβS inhibited the CCK-stimulated amylase release. Stimulation of permeabilized acini with 0.1 µM CCK induced similar morphological changes as in unpermeabilized acini. Incubation of permeabilized acini with GTPγS mimicked the CCK-induced changes, whereas a preincubation with GDPβS prevented the CCK effects on the acinar morphology. Inhibition of the small G protein rho, which activates p125 focal adhesion kinase, by Clostridium botulinum C3 transferase also prevented the CCK-stimulated morphological changes. Preincubation of intact acini with cell-permeable inhibitors of protein kinase C, MEK or p38MAPK, or with the intracellular calcium chelator BAPTA/AM was without significant effect on the CCK-stimulated changes. Conclusion: The CCK-induced morphological changes seem to be mediated by G protein signalling via the small G protein rho and the associated activation of p125 focal adhesion kinase.

The role of diagnostic radiology in pancreatitis

Acute pancreatitis is a frequent inflammatory and necrotic process of pancreas and peripancreatic field. To detect the presence of infected or sterile necrotic components and hemorrhage of the pancreatic paranchyma is important for therapeutic approach. Chronic pancreatitis is characterized by irreversible exocrine dysfunction, progressive loss of pancreatic tissue and morphological changes of the pancreatic canal. Imaging modalities play a primary role in the management of both acute and cronic pancreatitis. CT and MR imaging confirm the diagnosis and detect the severity of disease. In chronic pancreatitis, MRCP after Secretin administration, Spiral CT and endoscopic US seems to replace diagnostic ERCP. However differentiation of pseudotumor of chronic pancreatitis from the pancreatic carcinoma is difficult with either imaging modalities.

Transgenic expression of epidermal growth factor and keratinocyte growth factor in beta-cells results in substantial morphological changes.

The upregulation of a limited number of growth factors in our interferon-gamma transgenic model for regeneration within the pancreas lead us to propose that these factors are important during pancreatic regeneration. In this study, we have assessed the influence of two growth factors within the pancreas, epidermal growth factor (EGF) and keratinocyte growth factor (KGF), by ectopically expressing these proteins under the control of the human insulin promoter in transgenic mice. This beta-cell-targeted expression of either EGF or KGF resulted in significant morphological changes, including cellular proliferation and disorganized islet growth. Intercrossing the individual Ins-EGF and Ins-KGF transgenic mice resulted in more profound changes in pancreatic morphology including proliferation of pancreatic cells and extensive intra-islet fibrosis. Insulin-producing beta-cells were found in some of the ducts of older Ins-EGF and Ins-EGFxKGF transgenic mice, and amylase-producing cells were observed within the islet structures of the double transgenic mice. These data suggest that both EGF and KGF are capable of affecting pancreatic differentiation and growth, and that co-expression of these molecules in islets has a more substantial impact on the pancreas than does expression of either growth factor alone.

Ischemia and reperfusion in pancreas.

Ischemic diseases of heart and brain are the primary causes of mortality in industrialized nations. The ischemic injury with the consecutive reperfusion is responsible for the disturbance of microcirculation with ensuing tissue damage and organ dysfunction. Recent evidence suggests that oxygen-derived free radicals and activated polymorphonuclear leukocytes produced in ischemic tissue are instrumental in the development of ischemic cell injury. In pancreas, ischemia/ reperfusion is proposed as a potentially damaging factor accounting in part for the pathogenesis of acute pancreatitis. Apart from ischemia/reperfusion injury, the kallikrein-kinin system mediates acute inflammation associated with enhanced capillary permeability and accumulation of polymorphonuclear leukocytes, cardinal features of ischemia/reperfusion injury also in acute pancreatitis. Therefore, it seems reasonable to use bradykinin-antagonists to influence postischemic reperfusion injury of the pancreas. In the following, we describe the pathophysiology of ischemia/reperfusion injury with special reference to the pancreatic microcirculation and morphological changes as observed in a model of complete and reversible ischemia. Furthermore, we will discuss the effects of two bradykinin-antagonists (HOE 140 and CP-0597) on functional integrity of the pancreas after ischemia/ reperfusion.

Influence of changes in pancreatic tissue morphology and capillary blood flow on antibiotic tissue concentrations in the pancreas during the progression of acute pancreatitis.

The ability of an antibiotic to reach bactericidal concentrations in tissue depends on numerous factors including tissue composition and regional perfusion. Although necrotising pancreatitis is characterised by progression of pancreatic necrosis over at least 96 hours and microcirculatory alterations, the impact of these changes on the concentration of antibiotics in the pancreas has not yet been investigated. To determine and compare pancreatic tissue concentrations of imipenem and cefotaxime at different stages of acute necrotising pancreatitis in an animal model that has been shown to mimic closely the pathomorphological and bacteriological features of severe human pancreatitis. Acute necrotising pancreatitis was induced in rats by a standardised intraductal infusion of glycodeoxycholic acid and intravenous cerulein. Six hours (n = 16) and 48 hours (n = 16) after induction of pancreatitis, the animals were randomised for intravenous therapy with either imipenem or cefotaxime. Fifteen minutes after injection of the antibiotic, the animals were killed. Blood and the head of the pancreas were collected for determining imipenem or cefotaxime in serum and tissue; the splenic portion of the pancreas was prepared for histological examination. In an additional set of identically treated animals, pancreatic capillary blood flow (PCBF) was assessed by intravital microscopy before induction of acute necrotising pancreatitis and at the time of antibiotic therapy. Imipenem accumulates in the pancreas in the initial phase of acute necrotising pancreatitis characterised by pronounced oedema and decreased PCBF, and tends to decrease with resolution of the oedema and the progression of acinar cell necrosis in the later course of the disease. Concentrations of cefotaxime are low in oedematous pancreatic tissue early after induction of acute necrotising pancreatitis and increase with the resolution of oedema and normalisation of PCBF. Concentrations of antibiotics in the pancreas vary in acute necrotising pancreatitis, depending on changes in pancreatic tissue morphology and capillary blood flow. This suggests that antibiotic tissue concentrations may not be consistent from one agent to another and that efficacy of antibiotics in acute pancreatitis cannot be estimated solely on the basis of their pharmacological and microbiological properties.

Ligation-Induced Acute Pancreatitis Increases Pancreatic and Circulating Trypsinogen Activation Peptides

Ligation of the common bile–pancreatic duct induces hyperamylasemia and acute pancreatitis in rats. Pancreatic morphologic changes include edema, acinar cell damage, and mild inflammation. The pathogenesis of acute pancreatitis in this model is not understood, but may involve altered secretion and intrapancreatic activation of acinar proteases. We hypothesized that trypsinogen activation, measured by the production of plasma and pancreatic trypsinogen activation peptides (TAP), occurs early in this model. We performed the following experiments: rats were prepared with (1) bile–pancreatic ducts ligated and (2) ducts dissected but not ligated (sham). Rats were killed after 6, 24, and 48 hr. Serum amylase was measured and histologic sections were analyzed for morphologic changes. TAP was measured in both serum and pancreatic tissue homogenates using a specific polyclonal anti-TAP antibody in an enzyme-linked immunosorbant assay. After 6, 24, and 48 hr of bile–pancreatic duct ligation, hyperamylasemia and acute morphologic changes of acute pancreatitis were observed. Evidence of acinar cell destruction was not evident until 48 hr after ligation. Levels of serum and pancreatic tissue TAP were significantly elevated at both 24 and 48 hr after ligation compared to those of sham. We conclude that increased intrapancreatic trypsinogen activation occurs early in this form of experimental acute pancreatitis and that it occurs prior to evidence of acinar cell destruction. These data and observations support the possibility that intrapancreatic protease activation contributes to the pathogenesis of ligation-induced acute pancreatitis.

Bile and pancreatic juice replacement ameliorates early ligation-induced acute pancreatitis in rats

In healthy rats, combined bile and pancreatic juice diversion from gut has a synergistic rather than additive effect on stimulation of exocrine pancreatic protein secretion. We hypothesized that exclusion of combined bile and pancreatic juice from gut exacerbates bile and pancreatic-duct ligation-induced acute pancreatitis in rats to a greater extent than exclusion of either bile or pancreatic juice alone. Bile and pancreatic juice (obtained fresh from donor rats) were replaced, separately or together, via a duodenal fistula beginning immediately before 6 hours of duct ligation. Pancreatic morphologic changes were evaluated with an acute pancreatitis histology score and morphometric quantitation of acinar-cell necrosis. Plasma amylase and cholecystokinin concentrations and pancreatic subcellular distribution of cathepsin B activity were determined. Characteristics of bile and pancreatic juice obtained from donor rats were also studied. Combined bile and pancreatic juice replacement limited the increase in acute pancreatitis histology score by 77%, acinar cell necrosis by 95%, hyperamylasemia by 77%, and hypercholecystokininemia by 99%, while preventing subcellular redistribution of cathepsin B. Amelioration of pancreatic morphologic changes was significantly greater with combined bile and pancreatic juice replacement than with replacement of either bile or pancreatic juice alone. In this experimental corollary of early gallstone-induced acute pancreatitis, combined bile and pancreatic juice exclusion from gut contributes to disease pathogenesis to a greater extent than exclusion of either bile or pancreatic juice alone.