Pancreatic Duct Ligation Research Articles

Oxidative stress and NO generation in the rat pancreatitis induced by pancreatic duct ligation

The interaction between nitric oxide (NO) and superoxides is critical in the development of an acute pancreatitis. Previously, we reported that the expression of superoxides and of the NO-generating enzyme (NO synthase, NOS) was up-regulated in the human pancreatitis, especially within the exocrine compartment indicating an exceptional susceptibility of the exocrine parenchyma to oxidative stress. The aim of the present study was to compare the regulation of NO signalling pathways in the human pancreatitis and in an animal model of an acute pancreatitis induced by pancreatic duct ligation (PDL) in rats. In the PDL-induced rat pancreatitis, we revealed a similar pattern of oxidative stress and NOS up-regulation in acinar and in ductal compartments, like in the human pancreatitis. This demonstrates that the PDL-induced rat pancreatitis is a proper model for further studies of acute pancreatitis development in humans.

Acute obstructive pancreatitis after pancreas-sparing total duodenectomy in a patient with pancreas divisum: a case report.

BackgroundPancreas-sparing total duodenectomy (PSTD) is an ideal recommended procedure for patients with multiple duodenal adenomas or early duodenal cancer. We herein report a rare but serious complication of PSTD.Case presentationA 20-year-old woman with duodenal adenocarcinoma underwent PSTD. On postoperative day one, she complained of severe abdominal pains. Her serum amylase and serum pancreatic amylase levels were extremely elevated (Amy, 1296 IU/L; P-Amy, 1273 IU/L). With contrast enhanced CT, acute obstructive pancreatitis with pancreas divisum due to the ligation of the dorsal pancreatic duct was highly suspected. An emergency operation was performed to relieve the pancreatic duct obstruction, and an additional anastomosis between the dorsal pancreatic duct and jejunum was performed. The patient’s postoperative course was mostly uneventful, and her discomfort improved immediately.ConclusionWhen we perform pancreas-sparing total duodenectomy, some form of pancreatography is necessary to exclude pancreas divisum.

STAT3 modulates β-cell cycling in injured mouse pancreas and protects against DNA damage.

Partial pancreatic duct ligation (PDL) of mouse pancreas induces a doubling of the β-cell mass mainly through proliferation of pre-existing and newly formed β-cells. The molecular mechanism governing this process is still largely unknown. Given the inflammatory nature of PDL and inflammation-induced signaling via the signal transducer and activator of transcription 3 (STAT3), the activation and the role of STAT3 in PDL-induced β-cell proliferation were investigated. Duct ligation stimulates the expression of several cytokines that can act as ligands inducing STAT3 signaling and phosphorylation in β-cells. β-Cell cycling increased by conditional β-cell-specific Stat3 knockout and decreased by STAT3 activation through administration of interleukin-6. In addition, the level of DNA damage in β-cells of PDL pancreas increased after deletion of Stat3. These data indicate a role for STAT3 in maintaining a steady state in the β-cell, by modulating its cell cycle and protection from DNA damage.

Korean red ginseng ameliorated experimental pancreatitis through the inhibition of hydrogen sulfide in mice.

Effective therapy to treat acute pancreatitis (AP) or to prevent its recurrence/complication is still not available. Based on previous results that suggest that: i) hydrogen sulfide (H2S) levels were significantly increased in pancreatitis and gastritis and ii) Korean red ginseng (KRG) efficiently attenuated Helicobacter pylori-associated gastritis through the suppressive actions of H2S, we hypothesized that KRG can ameliorate experimental pancreatitis through suppression of H2S generation. C57BL/6 mice were pre-administered KRG and then subjected to cerulein injection or pancreatic duct ligation (PDL) to induce pancreatitis. Blood and pancreas tissues were collected and processed to measure serum levels of amylase, lipase and myeloperoxidase and the concentration of H2S and the levels of various inflammatory cytokine in pancreatic tissues of mice with induced AP. KRG significantly inhibited NaHS-induced COX-2 and TNF-α mRNA in pancreatic cells, but dl-propargylglycine did not. KRG ameliorated cerulein-induced edematous pancreatitis accompanied with significant inactivation of NF-κB and JNK in pancreatic tissues of C57BL/6 mice (p<0.001) and also significantly ameliorated PDL-induced necrotizing pancreatitis (p<0.01); in both conditions, the significant suppression of H2S resulting from KRG pretreatment afforded rescuing outcomes. Along with suppressed levels of H2S consequent to depressed expressions of CBS and CSE mRNA, KRG administration efficiently decreased the serum level of amylase, lipase, and myeloperoxidase and the expression of inflammatory cytokines in animal models of mild or severe AP. These results provide evidence for the preventive and therapeutic roles of KRG against AP mediated by H2S suppression.

Decreased insulin secretion and glucose clearance in exocrine pancreas-insufficient pigs.

The effect of exocrine pancreatic function on the glucose-mediated insulin response and glucose utilization were studied in an exocrine pancreas-insufficient (EPI) pig model. Five 10-week-old EPI pigs after pancreatic duct ligation and 6 age-matched, non-operated control pigs were used in the study. Blood glucose, plasma insulin and C-peptide concentrations were monitored during meal (MGTT), oral (OGTT) and intravenous (IVGTT) glucose tolerance tests. Upon post-mortem examination, the pancreatic remnants of the EPI pigs showed acinar fibrotic atrophy but normal islets and β-cell morphology. The EPI pigs displayed increased fasting glucose concentrations compared with control animals (6.4 ± 0.4 versus 4.8 ± 0.1 mmol l(-1) , P < 0.0001) but unchanged insulin concentrations (2.4 ± 0.6 versus 2.1 ± 0.2 pmol l(-1) ). During the OGTT and IVGTT, the EPI pigs showed slower, impaired glucose utilization, with the disruption of a well-timed insulin response. Plasma C-peptide concentrations confirmed the delayed insulin response during the IVGTT in EPI pigs. Oral pancreatic enzyme supplementation (PES) of EPI pigs improved glucose clearance during IVGTT [AUC(glucose) 1295 ± 70 mmol l(-1) × (120 min) in EPI versus 1044 ± 32 mmol l(-1) × (120 min) in EPI + PES, P < 0.0001] without reinforcing the release of insulin [AUC(C-peptide) 14.4 ± 3.8 nmol l(-1) × (120 min) in EPI versus 6.4 ± 1.3 nmol l(-1) × (120 min) in EPI + PES, P < 0.002]. The results suggest the existence of an acino-insular axis regulatory communication. The presence of pancreatic enzymes in the gut facilitates glucose utilization in an insulin-independent manner, indicating the existence of a gut-derived pancreatic enzyme-dependent mechanism involved in peripheral glucose utilization.

Long-term evolution of acinar-to-ductal metaplasia and β-cell mass after radiofrequency-assisted transection of the pancreas in a controlled large animal model.

Pancreatic duct ligation (PDL) has been used as a model of chronic pancreatitis and as a model to increase β-cell mass. However, studies in mice have demonstrated acinar regeneration after PDL, questioning the long-term validity of the model. We aim to elucidate whether RF-assisted transection (RFAT) of the main pancreatic duct is a reliable PDL model, both in short (ST, 1-month) and long-term (LT, 6-months) follow-ups. Eleven pigs were subjected to RFAT. Biochemical (serum/peripancreatic amylase and glucose) and histological changes (including a semiautomatic morphometric study of over 1000 images/pancreas and IHC analysis) were evaluated after ST or LT follow-up and also in fresh pancreas specimens that were used as controls for 1 (n = 4) and 6 months (n = 6). The distal pancreas in the ST was characterized by areas of acinar-to-ductal metaplasia (56%) which were significantly reduced at LT (21%) by fibrotic replacement and adipose tissue. The endocrine mass showed a normal increase. RFAT in the pig seems to be an appropriate PDL model without restoration of pancreatic drainage or reduction of endocrine mass.

Yarrowia lipolytica Lipase 2 Is Stable and Highly Active in Test Meals and Increases Fat Absorption in an Animal Model of Pancreatic Exocrine Insufficiency

Pancreatic exocrine insufficiency (PEI) reduces pancreatic secretion of digestive enzymes, including lipases. Oral pancreatic enzyme replacement therapy (PERT) with pancreatin produces unsatisfactory results. The lipase 2 produced by the yeast Yarrowia lipolytica (YLLIP2; GenBank: AJ012632) might be used in PERT. We investigated its ability to digest triglycerides in a test meal and its efficacy in reducing fecal fat in an animal model of PEI. YLLIP2 was produced by genetically engineered Y lipolytica and purified from culture media. YLLIP2 or other gastric (LIPF) and pancreatic (PNLIPD) lipases were added to a meal paste containing dietary triglycerides, at a range of pH values (pH 2-7), with and without pepsin or human bile and incubated at 37°C. We collected samples at various time points and measured lipase activities and stabilities. To create an animal model of PEI, steatorrhea was induced by embolization of the exocrine pancreas gland and pancreatic duct ligation in minipigs. The animals were given YLLIP2 (1, 4, 8, 40, or 80 mg/d) or pancreatin (100,000 US Pharmacopeia lipase units/d, controls) for 9 days. We then collected stool samples, measured fat levels, and calculated coefficient of fat absorption (CFA) values. YLLIP2 was highly stable and poorly degraded by pepsin, and had the highest activity of all lipases tested on meal triglyceride at pH 4-7 (pH 6 with bile: 94 ± 34 U/mg; pH 4 without bile: 43 ± 13 U/mg). Only gastric lipase was active and stable at pH 3, whereas YLLIP2 was sensitive to pepsin hydrolysis after pH inactivation. From invitro test meal experiments, the lipase activity of YLLIP2 (10 mg) was estimated to be equivalent to that of pancreatin (1200 mg; 100,000 US Pharmacopeia units) at pH 6. In PEI minipigs, CFA values increased from 60.1% ± 9.3% before surgery to 90.5% ± 3.2% after administration of 1200 mg pancreatin (P < .05); CFA values increased to a range of 84.6% ± 3.0% to 90.0% ± 3.8% after administration of 4-80 mg YLLIP2 (P < .05). The yeast lipase YLLIP2 is stable and has high levels of activity against test meal triglycerides in a large pH range, with and without bile. Oral administration of milligram amounts of YLLIP2 significantly increased CFA values, similar to that of 1.2 g pancreatin, in a minipig model of PEI.

Surgical Injury to the Mouse Pancreas through Ligation of the Pancreatic Duct as a Model for Endocrine and Exocrine Reprogramming and Proliferation.

Expansion of pancreatic beta cells in vivo or ex vivo, or generation of beta cells by differentiation from an embryonic or adult stem cell, can provide new expandable sources of beta cells to alleviate the donor scarcity in human islet transplantation as therapy for diabetes. Although recent advances have been made towards this aim, mechanisms that regulate beta cell expansion and differentiation from a stem/progenitor cell remain to be characterized. Here, we describe a protocol for an injury model in the adult mouse pancreas that can function as a tool to study mechanisms of tissue remodeling and beta cell proliferation and differentiation. Partial duct ligation (PDL) is an experimentally induced injury of the rodent pancreas involving surgical ligation of the main pancreatic duct resulting in an obstruction of drainage of exocrine products out of the tail region of the pancreas. The inflicted damage induces acinar atrophy, immune cell infiltration and severe tissue remodeling. We have previously reported the activation of Neurogenin (Ngn) 3 expressing endogenous progenitor-like cells and an increase in beta cell proliferation after PDL. Therefore, PDL provides a basis to study signals involved in beta cell dynamics and the properties of an endocrine progenitor in adult pancreas. Since, it still remains largely unclear, which factors and pathways contribute to beta cell neogenesis and proliferation in PDL, a standardized protocol for PDL will allow for comparison across laboratories.

Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice.

Chronic pancreatitis (CP) is a devastating disease with no treatments. Experimental models have been developed to reproduce the parenchyma and inflammatory responses typical of human CP. For the present study, one objective was to assess and compare the effects of pancreatic duct ligation (PDL) to those of repetitive cerulein (Cer)-induced CP in mice on pancreatic production of bone morphogenetic protein-2 (BMP2), apelin, and parathyroid hormone-related protein (PTHrP). A second objective was to determine the extent of cross talk among pancreatic BMP2, apelin, and PTHrP signaling systems. We focused on BMP2, apelin, and PTHrP since these factors regulate the inflammation-fibrosis cascade during pancreatitis. Findings showed that PDL- and Cer-induced CP resulted in significant elevations in expression and peptide/protein levels of pancreatic BMP2, apelin, and PTHrP. In vivo mouse and in vitro pancreatic cell culture experiments demonstrated that BMP2 stimulated pancreatic apelin expression whereas apelin expression was inhibited by PTHrP exposure. Apelin or BMP2 exposure inhibited PTHrP expression, and PTHrP stimulated upregulation of gremlin, an endogenous inhibitor of BMP2 activity. Transforming growth factor-β (TGF-β) stimulated PTHrP expression. Together, findings demonstrated that PDL- and Cer-induced CP resulted in increased production of the pancreatic BMP2, apelin, and PTHrP signaling systems and that significant cross talk occurred among pancreatic BMP2, apelin, and PTHrP. These results together with previous findings imply that these factors interact via a pancreatic network to regulate the inflammation-fibrosis cascade during CP. More importantly, this network communicated with TGF-β, a key effector of pancreatic pathophysiology. This novel network may be amenable to pharmacologic manipulations during CP in humans.

243 Effects of pancreatic exocrine insufficiency on growth, bone density and IGF 1 serum levels of young growing pigs – used as a model for children

Objectives As osteoporosis is a relevant issue even in juvenile CF patients this study aimed to test effects of pancreatic exocrine insufficiency (PEI) on growth and bone density (BD) in piglets – used as a model for children. Methods In 8 piglets aged 8 weeks PEI was induced by pancreatic duct ligation (PL), 4 sham operated pigs served as controls (C). 4 of the PL-pigs (PL+E) received Creon® (∼6300 IU lipase/g cfa) while PL (n = 4) received no enzymes. A complete diet was pair fed for 8 weeks, the last 3 weeks it was offered ad libitum. All animals were treated every 2nd week with 3 ml of Ursovit®, 3 ml Vitamin-B-complex and 3.3 mg vitamin K1. In week 11 post OP pigs were euthanised. Left tibia was taken and analysed by peripheral quantitative computer tomography for total bone mineral content (BMC) and cortex mineral content (CMC) at 50% of length. Results are given as mean. Results Body weight (kg) was higher in C (79.7) than in PL+E (62.9) and PL (51.3). Body length (nose to tail, cm) was highest in C (128) and shortest in PL (117). BMC (mg/cm) was significantly lower in PL (191) than in C (237). PL+E pigs were intermediate (206), not different from C or PL. CMC was significantly lower in PL (164) compared to C (211), too, while PL+E (178) did not differ from both groups. IGF 1 levels (ng/ml serum) were highest in C (473) and lowest in PL (187). Conclusion BD was reduced in PL even there were no other predisposing factors (bed rest, corticoid treatment, unbalanced diet). Although animals showed no clinical symptoms this study indicates that PEI itself is a risk factor for osteoporosis. Enzyme supplementation improved growth and BD.

241 Changes in fatty acid pattern of depot fat tissue in young pancreatic duct ligated pigs – used as a model for humans with pancreatic exocrine insufficiency

Objectives Most CF patients suffer from pancreatic exocrine insufficiency (PEI) causing maldigestion and malabsorption of fat. PEI patients are prone to deficiency in essential fatty acids. This study aimed to test whether fatty acid (FA) pattern of fat tissue is affected in pigs with PEI induced by pancreatic duct ligation (PL). Methods 9 piglets underwent surgery at the age of 7 weeks [n = 5 sham OP = controls; n = 4 PL (PL7)], 3 pigs underwent PL when aged 16 weeks (PL16). No pancreatic enzyme therapy was given to PL-pigs. A complete diet was fed containing soy oil and linseed oil (total 115 g crude fat/kg diet dm). All pigs were euthanized at the age of 26 weeks and neck fat tissue was sampled. FA were analysed by GC (ATI Unicam 610, SP-2560 column, Supelco; carrier gas: N). Results Total tract crude fat digestibility (%) was reduced in PL7 (33.4) and PL16 (38.4) compared to controls (80.1). Although diet fed and age at euthanasia were identical, FA pattern of fat tissue showed significantly changes in PL7. Saturated FA (C16:0 and C18:0) increased, while C18:3n3 decreased. Conclusion The increased C16:0 and C18:0 content of fat tissue in PL7 is supposed to be an effect of the relatively higher rate of de novo fat synthesis (Wood et al. 2008) in PL pigs. The fact that in PL16 pigs FA pattern did not differ from controls (except for an increase of C18:0) indicates that these changes need some time or are related to the age when PEI is induced. Whether the finding of the changes in FA pattern of the neck fat tissue in PL7 is a result of affected digestion of different FA or impaired metabolism after absorption is yet unclear.

242 Effects of experimentally induced pancreatic exocrine insufficiency on digestibility of electrolytes (praecaecal/total tract), urinary electrolyte content and acid-base status in young pigs – used as a model for children

Objectives Pancreatic exocrine insufficiency (PEI) affects absorption of electrolytes. Formation of soaps (due to reduced digestibility of fat) and higher amount of digesta resulting in higher losses of faecal water causes increased losses of electrolytes. As CF patients often suffer from PEI this aspect is of interest. Methods 14 piglets were used in this study. Pancreatic duct ligation (PL) was performed in 5 pigs at the age of 7 weeks (PL7) while 4 pigs underwent surgery at an age of 16 weeks (PL16). None of the PL-pigs received enzyme therapy. A complete diet was fed. All animals were euthanized at the age of 26 weeks. Results Result are given as mean±SD in the table. Controls PL7 PL16 Na digestibility (%) ileal −303±122 −644±271 −377±137 faecal 67.7±1.02 12.2±47.3 10.8±12.3 K digestibility (%) ileal 77.3±1.56 63.4±13.6 73.0±8.03 faecal 78.2±3.68 53.6±13.7 53.6±6.88 pH of urine 8.03±0.139 5.96±0.530 6.67±1.12 Urine net base excretion (UNBE) −10.5±7.55 150±29.8 −49.5±48.2 Na (mmol/L urine) 36.1±20.8 15.2±10.3 14.7±14.7 K (mmol/L urine) 126±56.2 151±48.1 122±98.2 Na:K in urine 0.326±0.166 0.114±0.081 0.170±0.121 Conclusion PEI caused a marked reduction of digestibility of Na and K. In some animals negative digestibility rates were observed. The lower urinary pH and UNBE in PL-pigs indicate massive changes in acid–base status, the lower ratio of Na:K in urine implicates that renal excretion is minimised in PL-pigs to compensate for the lower Na digestibility. This study clearly shows the manifold effects of PEI on electrolyte and acid–base status.

Monitoring changes in plasma levels of pancreatic and intestinal enzymes in a model of pancreatic exocrine insufficiency – induced by pancreatic duct-ligation – in young pigs

PurposePlasma levels of pancreatic and intestinal enzymes were measured after pancreatic duct ligation (PDL) to monitor pancreatic exocrine insufficiency (PEI) in a model using young pigs. Material/methodsFive, 6 week-old pigs (10.9±0.2kg), underwent PDL while age-matched, un-operated pigs were used as controls. Plasma levels of immunoreactive cationic trypsinogen (IRCT), amylase, lipase, and diamine oxidase (DAO) activities were analyzed for 48 days after PDL, including 1 week of oral pancreatic enzyme supplementation (PES) with Creon®. ResultsPDL resulted in an arrested body growth and a rapid surge of pancreatic enzymes (IRCT, amylase and lipase) into the plasma. Nine days after PDL, the plasma levels of these pancreatic enzymes had decreased. IRCT then remained below the level in un-operated pigs while amylase only fell below control at 25 days. The intestinally derived marker DAO and plasma protein levels were unaffected by PDL but DAO decreased slightly with time in PEI pigs. One-week of oral PES restored body growth, but had little effect on pancreatic enzyme plasma levels, except for a tendency towards increased DAO. ConclusionsThe study showed that PEI developed within 1–2 weeks after PDL and that only IRCT is a reliable plasma enzyme marker for this. The reduced plasma DAO indicated that PEI also affected the intestines, while PES therapy restored growth of the PDL pigs and slightly increased plasma DAO, suggesting an improved intestinal function.

Starch Origin and Thermal Processing Affect Starch Digestion in a Minipig Model of Pancreatic Exocrine Insufficiency.

Although steatorrhea is the most obvious symptom of pancreatic exocrine insufficiency (PEI), enzymatic digestion of protein and starch is also impaired. Low praecaecal digestibility of starch causes a forced microbial fermentation accounting for energy losses and meteorism. To optimise dietetic measures, knowledge of praecaecal digestibility of starch is needed but such information from PEI patients is rare. Minipigs fitted with an ileocaecal fistula with (n = 3) or without (n = 3) pancreatic duct ligation (PL) were used to estimate the rate of praecaecal disappearance (pcD) of starch. Different botanical sources of starch (rice, amaranth, potato, and pea) were fed either raw or cooked. In the controls (C), there was an almost complete pcD (>92%) except for potato starch (61.5%) which was significantly lower. In PL pcD of raw starch was significantly lower for all sources of starch except for amaranth (87.9%). Thermal processing increased pcD in PL, reaching values of C for starch from rice, potato, and pea. This study clearly underlines the need for precise specification of starch used for patients with specific dietetic needs like PEI. Data should be generated in suitable animal models or patients as tests in healthy individuals would not have given similar conclusions.

Peculiarities of death and regeneration of pancreas cells at early stages of alcoholic chronic pancreatitis

The study has been conducted on 39 white laboratory male rats which formed 5 groups: experimental occlusal pancreatitis caused by ligation of the main pancreatic duct (n = 6), experimental alcoholic pancreatitis caused by oral intake of alcohol (n = 6), against the background of an excess (n = 6) or deficiency (n = 6) of nitric oxide, as well as a control group (n = 15). This study provides the detailed description of the processes of death and regeneration in the islets of Langerhans, typical for early stages of the disease. The expression of the proliferation markers (PCNA and Neurogenin-3) has been analyzed using histological and immunohistochemical methods along with the changes of morphological structure, that led to initiation of the alcoholic chronic pancreatitis against the background of imbalance in NO-ergic regulatory system caused by an excess or deficiency of nitric oxide. It has been found that ligation of the pancreatic duct in the experiment reconstructedthe circumstances of chronic pancreatitis in rats and caused the activation of fibrosis and regeneration of endocrine and exocrine tissue. Compared with occlusion, the effects of ethanol on the pancreas also manifested in the activation of fibrogenesis, but the structural changes were negligible and could unlikely lead to advanced fibrosis and chronic pancreatitis in the future. On the other side, an imbalance of NO-system in alcoholic rats leads to disruption of the zymogens secretion in the acinar cells and dilatation of the capillary network in islets. Uneven distribution of zymogen granules may lead to their intracellular activation as evidenced by the deformation of acini and focal apoptosis without inflammatory response. In this case, violation of the key adaptive responses in the pancreas makes it more vulnerable to the effects of ethanol, its metabolites, and other environmental factors, and may increase the probability of chronic pancreatitis development. At the same time, forementioned process of cell death in the pancreas is considerably more prolonged, and long term course eliminates the activation of proliferation or functional tissue regeneration.

Inadvertent ligation of the main pancreatic duct: an extremely rare complication of choledochal cyst excision.

Pancreatic ductal injury is rare during choledochal cyst excision. Most cases present in the immediate postoperative period with pancreatic fistula or acute pancreatitis are managed conservatively. But, inadvertent ligation of the main pancreatic duct with subsequent recurrent pancreatitis and upstream dilatation of the pancreatic duct requiring a pancreatic ductal drainage operation has not been reported in the English literature. A 23-year-old female patient presented with recurrent episodes of upper abdominal pain for about 16months. She had a history of type-1 choledochal cyst excision 18months back. She was evaluated with abdominal ultrasound and magnetic resonance cholangiopancreatography (MRCP). MRCP showed hugely dilated main pancreatic duct with normal hepaticojejunostomy anastomosis. There was no residual cyst. MRCP findings were suggestive of stricture of the main pancreatic duct due to previous surgery. Endoscopic pancreatic ductal decompression failed. The patient was treated successfully with pancreaticogastrostomy. Postoperative recovery was uneventful. The patient was well at 24-month follow-up.

Evaluation of miR-216a and miR-217 as potential biomarkers of acute pancreatic injury in rats and mice

Mild injury of the exocrine pancreas is often asymptomatic and can be under- or mis-diagnosed. The pancreas-enriched microRNAs miR-216a and miR-217 were evaluated as potential serum biomarkers of exocrine pancreas injury in rodent models of acute pancreatitis induced by caerulein, l-arginine, and pancreatic duct ligation. Both microRNAs showed time- and dose- relevant responses to pancreatic injury and wider dynamic ranges of response than serum amylase or lipase. Pancreas-selective microRNAs were found to be relatively sensitive serum biomarkers of pancreatic injury in rodents with potentially greater specificity than the current standard assays.

Acinar cell-specific knockout of the PTHrP gene decreases the proinflammatory and profibrotic responses in pancreatitis

Pancreatitis is a necroinflammatory disease with acute and chronic manifestations. Accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic pancreatitis (CP). Pancreatic parathyroid hormone-related protein (PTHrP) levels are elevated in a mouse model of cerulein-induced AP. Here, we show elevated PTHrP levels in mouse models of pancreatitis induced by chronic cerulein administration and pancreatic duct ligation. Because acinar cells play a major role in the pathophysiology of pancreatitis, mice with acinar cell-specific targeted disruption of the Pthrp gene (PTHrP(Δacinar)) were generated to assess the role of acinar cell-secreted PTHrP in pancreatitis. These mice were generated using Cre-LoxP technology and the acinar cell-specific elastase promoter. PTHrP(Δacinar) exerted protective effects in cerulein and pancreatic duct ligation models, evident as decreased edema, histological damage, amylase secretion, pancreatic stellate cell (PSC) activation, and extracellular matrix deposition. Treating acinar cells in vitro with cerulein increased IL-6 expression and NF-κB activity; these effects were attenuated in PTHrP(Δacinar) cells, as were the cerulein- and carbachol-induced elevations in amylase secretion. The cerulein-induced upregulation of procollagen I expression was lost in PSCs from PTHrP(Δacinar) mice. PTHrP immunostaining was elevated in human CP sections. The cerulein-induced upregulation of IL-6 and ICAM-1 (human acinar cells) and procollagen I (human PSCs) was suppressed by pretreatment with the PTH1R antagonist, PTHrP (7-34). These findings establish PTHrP as a novel mediator of inflammation and fibrosis associated with CP. Acinar cell-secreted PTHrP modulates acinar cell function via its effects on proinflammatory cytokine release and functions via a paracrine pathway to activate PSCs.

Elongation of the small intestine in case of experimentally induced exocrine pancreatic insufficiency in young pigs? Effect of age at pancreatic duct ligation?

Elongation of the small intestine in case of experimentally induced exocrine pancreatic insufficiency in young pigs? Effect of age at pancreatic duct ligation?

IL-6-dependent proliferation of alpha cells in mice with partial pancreatic-duct ligation.

IL-6 was recently shown to control alpha cell expansion. As beta cells expand following partial pancreatic-duct ligation (PDL) in adult mice, we investigated whether PDL also causes alpha cells to expand and whether IL-6 signalling is involved. As alpha cells can reprogramme to beta cells in a number of beta cell (re)generation models, we examined whether this phenomenon also exists in PDL pancreas. Total alpha cell volume, alpha cell size and total glucagon content were evaluated in equivalent portions of PDL- and sham-operated mouse pancreases. Proliferation of glucagon(+) cells was assessed by expression of the proliferation marker Ki67. Inter-conversions between alpha and beta cells were monitored in transgenic mice with conditional cell-type-specific labelling. The role of IL-6 in regulating alpha cell proliferation was evaluated by in situ delivery of an IL-6-inactivating antibody. In response to PDL surgery, alpha cell volume in the ligated tissue was increased threefold, glucagon content fivefold and alpha cell size by 10%. Activation of alpha cell proliferation in PDL pancreas required IL-6 signalling. A minor fraction of alpha cells derived from beta cells, whereas no evidence for alpha to beta cell conversion was obtained. In PDL-injured adult mouse pancreas, new alpha cells are generated mainly by IL-6-dependent self-duplication and seldom by reprogramming of beta cells.