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Background: Outcome of severe acute pancreatitis (SAP) highly depends on the degree of systemic inflammation and organ failure. Although treatment approaches targeting the inflammatory cascade have failed in pancreatitis, recent studies suggest that extracorporeal cytokine adsorption effectively reduces concentrations of pro-inflammatory cytokines and potentially improves the outcome of sepsis., Methods: Sixteen patients with SAP, presenting within 7 days upon onset of pain, an APACHE-II score of ≥10 and ≥1 marker of poor prognosis, received 2 consecutive 24-h treatments with CytoSorb® extracorporeal cytokine adsorption (intervention group). Hemodynamics, organ failure, and mortality were compared with an APACHE-II score-matched retrospective control group of 32 patients., Results: The primary objective (20% decrease in the vasopressor dependency index or 20% increase in the cardiac index) was reached in 68.8% of the intervention and 28.1% of the control patients (p = 0.007), respectively. The cytokine adsorption significantly reduced IL-6 (-1998 pg/ml, p = 0.005) serum levels and resulted in stable CRP (p = 0.101) and decreased PCT (p = 0.003) levels in contrast to increased CRP (p = 0.014) and stable PCT levels (p = 0.695) in the control group. While mortality and improvement of respiratory failure were similar in both groups, renal failure significantly improved (change of KDIGO classification 72 h postcytokine adsorption [-1 vs. 0, p = 0.005]) and the SOFA score significantly decreased (day 5: -1.8 ± 2.0 vs. 1 ± 3.8, p = 0.013) in the intervention group., Conclusion: Cytokine adsorption might be an effective treatment option to stabilize hemodynamics in SAP. It decreases levels of the pro-inflammatory marker IL-6 and stabilizes organ function according to serial SOFA score assessments., (© 2022 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: Early identification of patients with acute severe pancreatitis is important for prompt and adequate treatment. Existing scores for pancreatitis are often laborious or require serial patient evaluation, whereas the qSOFA score, that was established to predict outcome in patients with suspected infection, is simple to perform., Aims and Methods: In this cohort study, we analyse the potential of the qSOFA score to predict outcome of patients with acute pancreatitis and refine the qSOFA score by rapid available laboratory parameters to the emergency room assessment of acute pancreatitis (ERAP) score. Validation was performed in a separate patient cohort., Results: In total 203 patients with acute pancreatitis were recruited. The qSOFA score has the potential to predict ICU admission (AUC = 0.730, p = 0.002) and organ failure (AUC = 0.799, p = 0.013) in acute pancreatitis. Respiratory rate, mental status, blood urea nitrogen and C-reactive protein are the rapid available parameters with the highest individual impact in binary logistic regression analyses. Their combination to the ERAP score can predict severity of acute pancreatitis according to the revised Atlanta classification (AUC = 0.689 ± 0.041, p < 0.001), ICU admission (AUC = 0.789 ± 0.067, p < 0.001), multi-organ dysfunction syndrome (AUC = 0.963 ± 0.024, p < 0.001) and mortality (AUC = 0.952 ± 0.028, p = 0.001). The performance and prognostic validity for organ failure and mortality were validated in an independent patient cohort., Conclusion: The qSOFA is a rapidly available prognostic score in acute pancreatitis with limited prognostic validity. A combination with the laboratory parameters BUN and CRP results in the new ERAP score with outstanding prognostic validity for multi-organ dysfunction syndrome and mortality., (© 2021. The Author(s).)

Stringent regulation of the inflammatory response is crucial for normal tissue regeneration. Here, we analyzed the role of Toll-like receptor 3 (TLR3) in pancreatic regeneration after acute pancreatitis (AP). AP was induced by caerulein treatment in mice with global TLR3 deficiency (TLR3 OFF ) or in mice re-expressing TLR3 exclusively in the myeloid cell lineage (TLR3 Mye ). Compared to WT mice, TLR3 OFF mice had a markedly increased formation of acinar-to-ductal metaplasia (ADM) that persisted until day 7 after initiation of AP. Pancreatic tissue of WT mice was completely regenerated after 5 days with no detectable ADM structures. The enhancing effect of TLR3-deficiency on ADM formation was closely linked with an increased and prolonged accumulation of macrophages in pancreata of TLR3 OFF mice. Importantly, the phenotype of TLR3 OFF mice was rescued in TLR3 Mye mice, demonstrating the causative role of myeloid cell selective TLR3 signaling. Moreover, in vitro stimulation of macrophages through TLR3 initiated cell death by a caspase-8-associated mechanism. Therefore, these findings provide evidence that TLR3 signaling in myeloid cells is sufficient to limit inflammation and ADM formation and to promote regeneration after AP. Notably, resolution of inflammation after AP was associated with macrophage sensitivity to TLR3-mediated cell death., (© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Background: The EGFR ligand betacellulin (BTC) has been previously shown to protect mice against experimentally induced acute pancreatitis (AP). BTC binds both autonomous ERBB receptors EGFR and ERBB4. In this study, we evaluated the mechanism underlying the protection from AP-associated inflammation in detail., Methods: AP was induced with cerulein or L-arginine and investigated in a pancreas-specific ERBB4 knockout and in an EGFR knockdown mouse model (Egfr Wa5/+ ). Pancreatitis was evaluated by scoring inflammation, necrosis, and edema, while microarrays were performed to analyze alterations in the transcriptome between mice with AP and animals which were protected against AP. The intracellular domain (ICD) of ERBB4 was analyzed in different cell compartments., Results: While the pancreas of BTC transgenic mice in the background of Egfr Wa5/+ is still protected against AP, the BTC-mediated protection is no longer present in the absence of ERBB4. We further demonstrate that BTC activates the ICD of ERBB4, and increases the expression of the extracellular matrix (ECM) proteins periostin and matrix gla protein as well as the ECM modulators matrix metalloproteinases 2 and 3, but only in the presence of ERBB4. Notably, the increased expression of these proteins is not accompanied by an increased ECM amount., Conclusions: These findings suggest that BTC derivates, as a drug, or the ERBB4 receptor, as a druggable target protein, could play an important role in modulating the course of AP and even prevent AP in humans.

Objectives: The importance of the Calcitonin-gene-related-peptide-pathway (CGRP) as neuronal modulator of innate immune responses in mice has been previously demonstrated. The CGRP-receptor is composed of two subunits: the receptor-activity-modifying-protein-1 (RAMP1) and the calcitonin-receptor-like-receptor (CLR). CGRP can influence immune cells and their capacity of producing inflammatory cytokines. Using a RAMP1 knockout-mouse (RAMP1 -/- ) we examined the role of the CGRP-receptor in the acute-phase of cerulein-induced pancreatitis., Methods: Hourly cerulein-injections for a period of 8 h in RAMP1 -/- and wild-type mice were performed. To compare severity and extent of inflammation in RAMP1 -/- and wild-type mice, histological analyses were done and cytokine levels were assessed using qRT-PCR 8 h, 24 h, 2 days, and 7 days post-cerulein-treatment. Furthermore, serum activities of LDH and lipase were determined., Results: After 8 h RAMP1 -/- mice showed a higher pancreas-to-body-weight-ratio, increased tissue edema and immune cell infiltration with higher amount of F4/80-positive cells as compared to wild-type mice. Overall infiltration of immune cells at 24 h was increased in RAMP1 -/- mice and composed predominantly of MPO-positive neutrophils. In addition, after 24 h RAMP1 -/- mice presented a higher pancreas-to-body-weight-ratio, higher expression of Ccl3, Il6, and Il1b and increased number of cleaved caspase 3 positive cells. Serum lipase correlated with the extent of tissue damage in RAMP1 -/- compared to wild-type mice 24 h post-cerulein treatment., Conclusion: Mice lacking RAMP1 showed increased inflammation, tissue edema, and pancreas injury particularly in the early phase of acute pancreatitis. This study highlights the essential role of CGRP for dampening the innate immune response in acute pancreatitis., (Copyright © 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Acute pancreatitis (AP) usually has a mild course with a mortality rate below 1%. However, around 10% of patients develop severe AP (SAP) involving extra-pancreatic tissues and other organ systems. The mortality of SAP is around 42%. The outcome of SAP is closely related to the development of systemic inflammation and consecutive organ failures. Most current therapies including fluid resuscitation, antimicrobial therapy, drainage procedures, and endoscopic management of complications are symptomatic rather than causative approaches, except sphincterotomy for gallstone pancreatitis. Regarding the high mortality of SAP and its close association with systemic inflammation, extracorporeal removal of inflammatory mediators is an appealing approach. Several recent studies have demonstrated that the CytoSorb adsorber effectively eliminates inflammatory cytokines, such as IL-1ß, IL-6, IL-8, IL-10, and TNF-alpha. Some of these trials suggested that therapy with CytoSorb might improve outcome, including a reduction in the vasopressor dosage and reversal of shock.Therefore, it is the objective of this study to evaluate the effectiveness of 2 consecutive 24 h-treatments with CytoSorb on hemodynamics in patients with early SAP., Methods: This study includes patients with early SAP (APACHE-II ≥10) and transpulmonary thermodilution hemodynamic monitoring (PiCCO; EV-1000) within a maximum of seven days from the onset of pain. Eligible patients will be treated with 2 consecutive periods of CytoSorb. A 20%-improvement in the vasopressor dependency index (VDI) - which relates is derived from mean arterial pressure (MAP) and catecholamine dosage - is the primary outcome. In addition to this clinical outcome, there are several laboratory (cytokine levels) and translational endpoints (including multiplex-ELISAs of numerous anti- and pro-inflammatory cytokines/chemokines and DNA analyses). Primary outcome analysis will compare the incidence of the primary endpoint in 30 patients from the intervention group to 60 matched controls with advanced hemodynamic monitoring recruited from recent studies in SAP within the same setting and the same centers., Discussion: A potential improvement in hemodynamics and/or other outcomes by CytoSorb would provide a new therapeutic option in the early treatment of SAP with a pathophysiological rationale., Trial Registration: This study was registered on March 17, 2017 (ClinicalTrials.gov Identifier: NCT03082469). URL: https://clinicaltrials.gov/ct2/show/NCT03082469., Version: V&#95;PACIFIC&#95;1.0 September 30, 2018.

Objectives: Animal models are essential to understand the pathogenesis of acute pancreatitis (AP) and to develop new therapeutic strategies. Although it has been shown that cerulein-induced AP is associated with pain in experimental animals, most experiments are carried out without any pain-relieving treatment because researchers are apprehensive of an interference of the analgetic agent with AP-associated inflammation. In light of the growing ethical concerns and the legal tightening regarding animal welfare during experiments, this attitude should be changed., Methods: Acute pancreatitis was induced by cerulein in the C57BL/6J and FVB/N mouse inbred strains. One group received vehicle only, and the other was treated with metamizol as analgetic agent. Pain sensation and parameters of AP were analyzed as well as the effect of metamizol in the pancreas and its actions in the brain., Results: We report that oral administration of metamizol protects cerulein-treated mice from abdominal pain without influencing the clinical and histopathological course of the disease. In addition, it could be shown that metamizol reduces the central pain response., Conclusions: This study reveals that oral administered metamizol has no influence on the cerulein-induced AP and can be given as an analgesic to increase animal welfare in experiments with induced AP.

Background & Aims: Under conditions of inflammation in the absence of micro-organisms (sterile inflammation), necrotic cells release damage-associated molecular patterns that bind to Toll-like receptors on immune cells to activate a signaling pathway that involves activation of IκB kinase and nuclear factor κB (NF-κB). Little is known about the mechanisms that control NF-κB activity during sterile inflammation. We analyzed the contribution of B-cell CLL/lymphoma 3 (BCL3), a transcription factor that associates with NF-κB, in control of sterile inflammation in the pancreas and biliary system of mice., Methods: Acute pancreatitis (AP) was induced in C57BL/6 (control) and Bcl3(-/-) mice by intraperitoneal injection of cerulein or pancreatic infusion of sodium taurocholate. We also studied Mdr2(-/-) mice, which develop spontaneous biliary inflammation, as well as Bcl3(-/-)Mdr2(-/-) mice. We performed immunohistochemical analyses of inflamed and noninflamed regions of pancreatic tissue from patients with AP or primary sclerosing cholangitis (PSC), as well as from mice. Immune cells were characterized by fluorescence-activated cell sorting analysis. Control or Bcl3(-/-) mice were irradiated, injected with bone marrow from Bcl3(-/-) or control mice, and AP was induced., Results: Pancreatic or biliary tissues from patients with AP or PSC had higher levels of BCL3 and phosphorylated RelA and IκBα in inflamed vs noninflamed regions. Levels of BCL3 were higher in pancreata from control mice given cerulein than from mice without AP, and were higher in biliary tissues from Mdr2(-/-) mice than from control mice. Bcl3(-/-) mice developed more severe AP after administration of cerulein or sodium taurocholate than control mice; pancreata from the Bcl3(-/-) mice with AP had greater numbers of macrophages, myeloid-derived suppressor cells, dendritic cells, and granulocytes than control mice with AP. Activation of NF-κB was significantly prolonged in Bcl3(-/-) mice with AP, compared with control mice with AP. Bcl3(-/-)Mdr2(-/-) mice developed more severe cholestasis and had increased markers of liver injury and increased proliferation of biliary epithelial cells and hepatocytes than Mdr2(-/-) mice. In experiments with bone marrow chimeras, expression of BCL3 by acinar cells, but not myeloid cells, was required for reduction of inflammation during development of AP. BCL3 inhibited ubiquitination and proteasome-mediated degradation of p50 homodimers, which prolonged binding of NF-κB heterodimers to DNA., Conclusions: BCL3 is up-regulated in inflamed pancreatic or biliary tissues from mice and patients with AP or cholangitis. Its production appears to reduce the inflammatory response in these tissues via blocking ubiquitination and proteasome-mediated degradation of p50 homodimers., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Most of the data about epidemiology, clinical presentation and treatment of autoimmune pancreatitis (AIP) is based on case series or small study groups. We therefore analyzed all cases of AIP treated at our clinic retrospectively., Methods: We searched our clinical database for the diagnosis pancreatitis between January 2007 and June 2014, selected patients with AIP and entered all relevant information in a database for statistical analysis., Results: In total 53 patients with AIP were treated at our institution, 62% with type 1 and 23% with type 2 AIP. Gender distribution was male/female 3.1:1 for type 1 and 1:1.2 for type 2 AIP. The median age was 63.0 and 32.5 years for type 1 and type 2 AIP, respectively. The most common symptom is abdominal pain particular in patients with type 2 AIP whereas jaundice was only apparent in patients with type 1 AIP. The international diagnostic criteria seem to facilitate diagnosis of AIP as unnecessary pancreatic surgery in patients with AIP decreases. In 62.6% of the patients therapy was indicated and 84.8% showed a response to initial therapy with steroids. Recurring disease occurred in 28.3% of the cases but only 3.8% suffered a second relapse. Permanent maintenance therapy with steroids or additional therapy with immunomodulatory drugs is successful in recurring disease., Conclusion: Our data further corroborate previous findings on epidemiology, clinical presentation and treatment of AIP. AIP is a well manageable autoimmune disease in most patients. Better biopsy techniques and simplified diagnostic criteria might further alleviate diagnosis of AIP., (Copyright © 2015 IAP and EPC. Published by Elsevier India Pvt Ltd. All rights reserved.)

Chronic pancreatitis is a disease of the pancreas in which recurrent inflammatory episodes result in replacement of pancreatic parenchyma by fibrous connective tissue. This fibrotic reorganization of the pancreas leads to a progressive exocrine and endocrine pancreatic insufficiency. In addition, characteristic complications arise, such as pseudocysts, pancreatic duct obstructions, duodenal obstruction, vascular complications, obstruction of the bile ducts, malnutrition and pain syndrome. Pain presents as the main symptom of patients with chronic pancreatitis. Chronic pancreatitis is a risk factor for pancreatic carcinoma. Chronic pancreatitis significantly reduces the quality of life and the life expectancy of affected patients. These guidelines were researched and compiled by 74 representatives from 11 learned societies and their intention is to serve evidence-based professional training as well as continuing education. On this basis they shall improve the medical care of affected patients in both the inpatient and outpatient sector. Chronic pancreatitis requires an adequate diagnostic workup and systematic management, given its severity, frequency, chronicity, and negative impact on the quality of life and life expectancy., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Autoimmune pancreatitis (AIP) was first classified as a defined disease entity in 1995. It accounts for approximately 2 % of cases of chronic pancreatitis (western world prevalence 36-41/100,000 inhabitants) and AIP is diagnosed in 2.4 % of pancreas resection specimens., Objectives: Presentation of strategies for diagnosis and treatment with focus on differentiation of AIP and pancreatic carcinoma., Methods: Selective literature research in PubMed regarding pathogenesis, diagnosis and treatment of AIP., Results: Key characteristics of AIP are recurrent jaundice due to obstructed bile ducts, histological evidence of fibrosis, a lymphoplasmocytic or granulocytic infiltrate and the response to steroid therapy. There are two distinctive forms of AIP: type I or lymphoplasmocytic sclerosing pancreatitis and type II or idiopathic duct centric pancreatitis. The IgG4 positive AIP type I belongs to the group of IgG4-related systemic diseases. Diagnosis of AIP is established according to the international consensus diagnostic criteria (ICDC) or HISORt (mnemonic standing for histology, imaging, serology, other organ involvement and response to therapy) criteria. Differentiation from pancreatic adenocarcinoma can be challenging. The standard treatment consists of corticosteroids and in some cases azathioprine can be added. In refractory disease rituximab is a further option. Treatment is indicated in patients with jaundice, systemic manifestation or persistent pain., Conclusion: Although AIP is increasingly being identified, the differentiation from pancreatic adenocarcinoma still remains difficult and in cases of a suspicion of neoplasia, resection should be favored. It can successfully be treated conservatively with steroids and rituximab.

Background/objectives: A rare, but life-threatening complication in pancreatitis is a spontaneous bleeding from intestinal vessels with or without previous formation of (pseudo-) aneurysms. And yet, the optimal diagnostic and therapeutic strategies remain unclear., Methods: We performed a retrospective analysis of all patients with pancreatitis and intraabdominal bleeding at a German tertiary referral center between January 2002 and December 2012., Results: Bleeding occurred in <1% (14/3,421) of patients with pancreatitis. Most involved vessels were arteria lienalis, arteria gastroduodenalis, and arteria pancreaticoduodenalis. All bleedings could be stopped by transcatheter arterial coil embolization. Recurrent bleeding after coil embolization occurred in 2/14 (14%) patients., Conclusions: In cases of intraabdominal hemorrhage in patients with pancreatitis, transcatheter arterial coil embolization should be considered as the first interventional procedure.

Objectives: This study aimed to explore the period between onset of pain and hospital-admission (pain-to-admission time) in patients with acute pancreatitis (AP), to investigate the prognostic value and associated factors of this time, and to ascertain the knowledge about the pancreas in these patients., Methods: An analysis of a prospective multicenter study was done, which included 188 patients with AP., Results: Median pain-to-admission time was 27 hours (interquartile range, 6.0-72.0). Median pain-to-admission time was significantly shorter in intensive care unit (ICU) patients (10 hours) compared to non-ICU patients (36 hours) (P = 0.045). Short pain-to-admission time was associated with high pain level. Median pain level (0, no pain; 10, maximal pain) was 8.0 (interquartile range, 7.0-10.0). Older age correlated with lower pain level (r = -0.26; P = 0.002). Multiple logistic regression analysis including the admission values for serum lipase and C-reactive protein and the corresponding interactions to the pain-to-admission time showed substantial discriminative ability regarding ICU admission (concordance index, 0.706; P = 0.006). 86% (112/130) knew that they have a pancreas, 72% (81/112) of these patients knew that AP exists, and 56% (45/81) recognized that AP is potentially fatal., Conclusions: Knowledge about AP in hospitalized AP patients is poor. Serum lipase and C-reactive protein in dependency of the pain-to-admission time might be a suitable predictor for severity of AP.

Acute lung injury (ALI) is an inflammatory disease with a high mortality rate. Although typically seen in individuals with sepsis, ALI is also a major complication in severe acute pancreatitis (SAP). The pathophysiology of SAP-associated ALI is poorly understood, but elevated serum levels of IL-6 is a reliable marker for disease severity. Here, we used a mouse model of acute pancreatitis-associated (AP-associated) ALI to determine the role of IL-6 in ALI lethality. Il6-deficient mice had a lower death rate compared with wild-type mice with AP, while mice injected with IL-6 were more likely to develop lethal ALI. We found that inflammation-associated NF-κB induced myeloid cell secretion of IL-6, and the effects of secreted IL-6 were mediated by complexation with soluble IL-6 receptor, a process known as trans-signaling. IL-6 trans-signaling stimulated phosphorylation of STAT3 and production of the neutrophil attractant CXCL1 in pancreatic acinar cells. Examination of human samples revealed expression of IL-6 in combination with soluble IL-6 receptor was a reliable predictor of ALI in SAP. These results demonstrate that IL-6 trans-signaling is an essential mediator of ALI in SAP across species and suggest that therapeutic inhibition of IL-6 may prevent SAP-associated ALI.

Background & Aims: The transcription factor nuclear factor-κB (NF-κB) (a heterodimer of NF-κB1p50 and RelA) is activated rapidly in acute pancreatitis (AP). However, it is not clear whether NF-κB promotes or protects against AP. We used the NF-κB inhibitor protein, inhibitor of κB (IκB)α, to study the roles of NF-κB in the development of AP in mice., Methods: IκBα or the combination of IκBα and RelA selectively were deleted from pancreas of mice using the Cre/locus of cross-over P strategy; cerulein or L-arginine were used to induce AP. We performed microarray analyses of the IκBα- and RelA-deficient pancreata. DNA from healthy individuals and patients with acute or chronic pancreatitis were analyzed for variants in coding regions of alpha-1-antichymotrypsin., Results: Mice with pancreas-specific deletion of IκBα had constitutive activation of RelA and a gene expression profile consistent with NF-κB activation; development of AP in these mice was attenuated and trypsin activation was impaired. However, AP was fully induced in mice with pancreas-specific deletion of IκBα and RelA. By using genome-wide expression analysis, we identified a cluster of NF-κB-regulated genes that might protect against the development of AP. The serine protease inhibitor 2A (Spi2a) was highly up-regulated in IκBα-deficient mice. Lentiviral-mediated expression of Spi2A reduced the development of AP in C57BL/6 and RelA-deficient mice. However, we did not correlate any variants of alpha-1-antichymotrypsin, the human homologue of Spi2a, with acute or chronic pancreatitis., Conclusions: Pancreas-specific deletion of IκBα results in nuclear translocation of RelA and reduces AP induction and trypsin activation in mice after administration of cerulein or L-arginine. Constitutive activation of RelA up-regulates Spi2A, which protects mice against the development of AP., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Endothelial injury is perhaps the inciting factor leading to the microangiopathic process that initiates thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS). TTP-HUS after postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is extremely rare, but potentially is life threatening. Here, we describe a case of a 23-year-old man with a history of choledocholithiasis, who developed TTP-HUS, 2 days after the onset of post-ERCP pancreatitis. It is important that physicians recognize TTP-HUS as one of the potential causes of acute kidney injury in cases of acute pancreatitis and post-ERCP pancreatitis for adult patients, especially when there is concomitant thrombocytopenia and hemolytic anemia. The early initiation of plasma exchange has a major impact on the survival and preservation of renal function. Exchange transfusion of fresh frozen plasma remains the cornerstone treatment of TTP-HUS.

The primary diseases of the pancreas include diabetes mellitus, acute and chronic pancreatitis, as well as pancreatic carcinoma. This review presents findings and emerging questions on the diseases of the pancreas obtained by the consortium of the Collaborative Research Center 518 (SFB 518), "Inflammation, Regeneration, and Transformation in the Pancreas" at the University of Ulm. During the last 12 years, the SFB 518 contributed considerably to the understanding of the cellular and molecular basis of pancreatic diseases and established the basis for the development of new strategies for prevention and causal therapy for diabetes, pancreatitis, and pancreatic cancer.

Background & Aims: Acute pancreatitis (AP) is a serious, unpredictable clinical problem, the pathophysiology of which is poorly understood. Here, we evaluate whether betacellulin (BTC), a ligand of the epidermal growth factor receptor also able to activate the proapoptotic ERBB4 receptor, can protect against experimental AP., Methods: AP was induced in transgenic mice overexpressing BTC (BTC-tg), control mice, or control mice after administration of recombinant BTC. The severity of pancreatitis was assessed by measurements of serum amylase and lipase and histologic grading. The involvement of the stress-activated protein kinase (SAPK) was evaluated by treating BTC-tg mice with an SAPK inhibitor before induction of AP., Results: BTC-tg mice showed increased apoptosis and proliferation in the exocrine pancreas, indicating an increased cell turnover. There was a marked, epidermal growth factor receptor-independent decrease in pancreas weight. After induction of AP by cerulein injection, BTC-tg mice showed a significantly lower increase in serum amylase and lipase levels as well as less pronounced tissue necrosis, edema, and inflammation, as compared to nontransgenic littermates. This protective effect, also confirmed in the L-arginine AP model, was associated with increased phosphorylation of SAPK and abrogated after treatment of BTC-tg mice with a SAPK inhibitor. Finally, the protective effect of BTC against AP was confirmed by treating nontransgenic mice with recombinant BTC., Conclusions: These findings indicate a potential application of the BTC/ERBB4 pathway for modulating the course of AP., (2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Acute pancreatitis is an inflammatory disorder, that is classically accompanied by abdominal pain and elevated serum lipase and amylase levels. While about 80% of the patients recover without complications, 20% develop severe local and systemic damages. Gallstone migration into the common bile duct and excessive alcohol abuse account for most of the cases, but also drugs have been shown to induce acute pancreatitis. Treatment of acute pancreatitis is only supportive, especially in severe episodes an interdisciplinary cooperation of gastroenterologists, radiologists, intensivists, and surgeons is required. The better understanding of the pathophysiology might merge into more tailored therapeutic procedures and improve the outcome of this disease.

Background: Infection of pancreatic necrosis is a life-threatening complication during the course of acute pancreatitis. In critically ill patients, surgical or extended endoscopic interventions are associated with high morbidity and mortality. Minimally invasive procedures on the other hand are often insufficient in patients suffering from large necrotic areas containing solid or purulent material. We present a strategy combining percutaneous and transgastric drainage with continuous high-volume lavage for treatment of extended necroses and liquid collections in a series of patients with severe acute pancreatitis., Patients and Methods: Seven consecutive patients with severe acute pancreatitis and large confluent infected pancreatic necrosis were enrolled. In all cases, the first therapeutic procedure was placement of a CT-guided drainage catheter into the fluid collection surrounding peripancreatic necrosis. Thereafter, a second endosonographically guided drainage was inserted via the gastric or the duodenal wall. After communication between the separate drains had been proven, an external to internal directed high-volume lavage with a daily volume of 500 ml up to 2,000 ml was started., Results: In all patients, pancreatic necrosis/liquid collections could be resolved completely by the presented regime. No patient died in the course of our study. After initiation of the directed high-volume lavage, there was a significant clinical improvement in all patients. Double drainage was performed for a median of 101 days, high-volume lavage for a median of 41 days. Several endoscopic interventions for stent replacement were required (median 8). Complications such as bleeding or perforation could be managed endoscopically, and no subsequent surgical therapy was necessary. All patients could be dismissed from the hospital after a median duration of 78 days., Conclusion: This approach of combined percutaneous/endoscopic drainage with high-volume lavage shows promising results in critically ill patients with extended infected pancreatic necrosis and high risk of surgical intervention. Neither surgical nor endoscopic necrosectomy was necessary in any of our patients., ((c) 2009 S. Karger AG, Basel.)

Background & Aims: The mechanisms for tissue regeneration and renewal after acute pancreatitis are not well understood but may involve activation of Notch signaling. To study the effect of Notch signaling ablation during acute experimental pancreatitis, we used a chemical and genetic approach to ablate Notch signaling in cerulein-induced pancreatitis in mice., Methods: Acute pancreatitis was induced by cerulein treatment in mice treated with the gamma-secretase inhibitor dibenzazepine or in conditional Notch1 knockout mice. Mice were characterized using immunohistologic, biochemical, and molecular methods. To investigate Notch and beta-catenin interaction, acinar 266-6 cells were analyzed using transfection and biochemical assays., Results: Loss of Notch signaling results in impaired regeneration after acute pancreatitis with fewer mature acinar cells in dibenzazepine-treated and Notch1-deficient mice in the regenerative phase 3 days after induction. beta-catenin expression was increased and prolonged during exocrine regeneration. Crosstalk between Notch and beta-catenin-mediated signaling was identified, with Notch1-IC inhibiting beta-catenin-mediated transcriptional activity. This inhibition was dependent on a functional RAM domain., Conclusions: Inhibition of Notch signaling in vivo leads to impaired regeneration of the exocrine pancreas after acute pancreatitis. Our results suggest an interaction of Notch and Wnt signaling in pancreatic acinar cells, providing evidence for a role of these pathways in the regulation of the maturation process of acinar cells.

Activation of the transcription factor NF-kappaB/Rel has been shown to be involved in inflammatory disease. Here we studied the role of RelA/p65, the main transactivating subunit, during acute pancreatitis using a Cre-loxP strategy. Selective truncation of the rela gene in pancreatic exocrine cells led to both severe injury of the acinar cells and systemic complications including lung and liver damage. Our data demonstrated that expression and induction of the protective pancreas-specific acute phase protein pancreatitis-associated protein 1 (PAP1) depended on RelA/p65. Lentiviral gene transfer of PAP1 cDNA reduced the extent of necrosis and infiltration in the pancreata of mice with selective truncation of RelA/p65. These results provide in vivo evidence for RelA/p65 protection of acinar cell death via upregulation of PAP1. Moreover, our data underscore the pancreas-specific role of NF-kappaB/Rel and suggest multidimensional roles of NF-kappaB/Rel in different cells and contexts during inflammation.

The systemic inflammatory response syndrome is responsible for pancreatitis-associated mortality. Recent in vitro and in vivo studies have suggested that pancreatic elastase is one missing link between the localized inflammatory process in the pancreas and distant organ dysfunction and failure. It has been shown that pancreatic elastase activates transcription factors, including NF-kappaB, and induces TNF-alpha secretion in myeloid cells via TLRs. In this study we demonstrate that a highly purified low endotoxin pancreatic elastase preparation (El-UP) failed both to activate NF-kappaB and to induce TNF-alpha release in RAW 264.7 cells and bone marrow-derived macrophages. In contrast, a less purified elastase preparation (El-IV) caused activation of NF-kappaB and was able to induce TNF-alpha release at very low concentrations. These effects were sensitive to pretreatment of the cells with polymyxin B and were resistant to heat inactivation. Endotoxin activity as determined by the Limulus amebocyte lysate assay was >3 orders of magnitude lower in the low endotoxin elastase preparation (El-UP) compared with less purified elastase preparations (El-IV). In contrast to contaminated elastase or LPS, elastase free of contamination (El-UP) failed to induce elevated serum TNF-alpha levels or pulmonary neutrophil infiltration after i.p. application in mice and did not induce lethality when coinjected with d-galactosamine. Failure of low endotoxin elastase (El-UP) to induce proinflammatory effects in vivo and in vitro was not due to functional inactivity of the elastase preparation, as determined by elastase activity assay. These results question current concepts of direct proinflammatory effects attributed to pancreatic elastase.

TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis by cross-linking of the two TRAIL receptors that contain a death domain, TRAIL-R1 and TRAIL-R2. TRAIL-R3 and TRAIL-R4 are receptors that do not transmit an apoptotic signal. Our aim was to determine the expression of TRAIL and its receptors in normal pancreas and chronic pancreatitis. We applied real-time PCR, immunohisto(cyto)chemistry, and nick-end labeling of apoptosis. In normal pancreas, a minor subset of acinar cells coexpressed TRAIL-R2 and TRAIL-R4, whereas ductular epithelium and interstitial fibroblast-like cells (FLC) expressed TRAIL-R4. TRAIL-R1 and TRAIL-R3 were not detected in normal pancreas. In chronic pancreatitis, the exocrine epithelium strongly expressed TRAIL-R1, -R2, -R4, and, to a lesser extent, TRAIL-R3. Islets focally neoexpressed TRAIL-R1 and -R2 and intensely expressed TRAIL-R4. Changes in TRAIL receptor expression were most pronounced in areas of inflammatory infiltration and active fibrosis. In normal pancreas, expression of TRAIL was low on the mRNA level and undetectable on the protein level. In chronic pancreatitis, FLC in areas of active fibrosis expressed TRAIL. In addition, apoptosis were most numerous in these areas. We show that these FLC are pancreatic stellate cells. Pancreatic stellate cells express TRAIL in vivo and in vitro, and TRAIL expression is enhanced by IFN-gamma. Our findings indicate that the TRAIL/TRAIL receptor system is likely to be involved in chronic pancreatitis and suggest that pancreatic stellate cells may directly contribute to acinar regression by inducing apoptosis of parenchymal cells in a TRAIL-dependent manner.

Acute pancreatitis is a serious disease with a high morbidity and an overall mortality rate of about 10%. However, in its most severe form, which is characterized by pancreatic necrosis, 20-30% of the patients die. Death is often the result of multiorgan dysfunction, including acute respiratory, kidney, and hepatic failure as well as generalized diffuse capillary leak water retention, hypoxia, and acid/base disturbance. The mechanisms by which distant organ systems are involved still remain obscure, but several lines of evidence suggest the participation of cytokines (IL-1, IL-6, and TNF-alpha) as a response to local tissue damage. A series of studies have now shed new light on the pivotal pathogenic role of the transcription factor NF-kappaB/Rel that binds to the promoter regions of many proinflammatory genes and regulates their transcription., (Copyright 2002 S. Karger AG, Basel and IAP)

Chronic pancreatitis is an inflammatory disease of the pancreas, characterized by a progressive destruction of the exocrine and endocrine pancreas, leading both to exocrine and endocrine insufficiency. In recent years, our knowledge of this disease has improved, an epidemiological link between chronic pancreatitis and pancreatic cancer has been established, and the molecular alterations underlying their pathogenesis have been partly revealed. Nevertheless, the differentiation of chronic inflammation of the pancreas from cancer of the pancreas remains a great challenge. This overview will point out the present knowledge of the molecular pathogenesis of chronic pancreatitis and pancreatic cancer and will focus on the role of molecular markers for differentiating chronic pancreatitis from pancreatic cancer., (Copyright 2001 S. Karger AG, Basel)

Background/aims: Chronic pancreatitis is an inflammatory disease of the exocrine pancreas associated with extensive fibrosis, enlarged pancreatic ducts, acinar cell degeneration, and the formation of tubular complexes. The molecular and biochemical alterations associated with these histological changes are not kown. Generally, the new family of TFF peptides (formerly known as P-domain peptides or trefoil factors) is aberrantly expressed during chronic inflammatory diseases of the gastrointestinal tract., Methods: Using human pancreatic tissues obtained from patients with chronic pancreatitis and murine pancreatic tissues obtained from transgenic mice overexpressing transforming growth factor alpha (TGF-alpha), the expression and cellular distribution of TFF1 was analysed using northern blot analysis, polymerase chain reaction (PCR), and immunohistochemistry., Results: In the normal human pancreas, TFF1 was scarce, with only a few ducts exhibiting cytoplasmic TFF1 immunoreactivity. In contrast, human chronic pancreatitis tissue specimens exhibited strong TFF1 immunoreactivity in ductal cells, areas of ductal hyperplasia, and tubular complexes. Semiquantitative PCR analysis of TFF1 mRNA levels showed enhanced expression of TFF1 in the pancreas of patients with chronic pancreatitis. Furthermore, TFF1 mRNA levels were detectable in the pancreas in four of five transgenic mice overexpressing TGF-alpha. In contrast, four of five wild type mice did not exhibit a TFF1 mRNA transcript. In addition, while no specific TFF1 immunoreactivity was present in the pancreas of the wild type mice, ductal epithelial cells and duct-like tubular complexes in the pancreas of the transgenic mice overexpressing TGF-alpha exhibited pronounced TFF1 immunoreactivity., Conclusions: Ductal cells and tubular complexes in pancreatic fibrosis express TFF1. As the 5'-flanking region of TFF1 contains an epidermal growth factor responsive enhancer region and the expression of epidermal growth factor and TGF-alpha is enhanced in pancreatic fibrosis, the enhanced expression of TFF1 in pancreatic fibrosis may be mediated by TGF-alpha.

Background & Aims: Recent evidence suggests that a number of rapid signaling cascades are initiated during secretagogue-induced pancreatitis. However, little is known about the nuclear events. The aim of this study was to explore activation of the transcription factor NF-kappaB/Rel after supramaximal stimulation with the cholecystokinin analogue cerulein in the pancreas., Methods & Results: Nuclear appearance of NF-kappaB/Rel-binding activity was detectable 15 minutes after cerulein injection. The DNA-binding activity consisted of NF-kappaB1 p50, NF-kappaB2 p52, and RelA p65 as judged by supershift assays and Western blot analysis. The onset and termination of NF-kappaB/Rel activation correlated with the degradation and reappearance of IkappaBalpha. Cerulein in supramaximal but not in physiological doses activated NF-kappaB/Rel in vitro. After blocking of NF-kappaB/Rel activation with pyrrolidine dithiocarbamate, the degree of morphological alterations was more pronounced than in controls, serum amylase and lactate dehydrogenase levels were significantly increased, and messenger RNA levels of pancreatitis-associated protein were more strongly induced, reflecting a more severe degree of pancreatitis. Similar results were obtained when N-acetyl-L-cysteine was used as an inhibitor of NF-kappaB activation., Conclusions: These data show that NF-kappaB/Rel is rapidly activated during cerulein pancreatitis. This activation may induce a self-defending genetic program before the onset of cellular injury, which might prevent higher degrees of damage of pancreatic acinar cells after secretagogue hyperstimulation.

Background: In patients suffering from chronic pancreatitis the risk for the development of pancreatic cancer ranges from 4 to 6 per cent. Various mutations are associated with pancreatic cancer, especially of p53 and K-ras. The incidence of these mutations in resected chronic pancreatitic tissue was investigated., Methods: In the present study DNA from 80 samples of tissue from patients with chronic pancreatitis was isolated and subjected to single-strand conformation polymorphism (SSCP) analysis of p53 exons 5-9 and restriction fragment length polymorphism analysis of K-ras (codon 12)., Results: No mutations in the K-ras gene were detected. On SSCP analysis, eight of 80 cases of chronic pancreatitis showed alterations (two in exon 5, four in exon 6, two in exon 7). DNA sequence analysis revealed one deletion of 21 amino acids (exon 5), four polymorphisms in exon 6 with no change in the amino acid sequence, one point mutation in exon 5, and two point mutations located in the intron between exons 6 and 7., Conclusion: These data show that in some cases of chronic pancreatitis mutations in the p53 gene occur without morphological evidence of pancreatic cancer.

Background/aims: The activation of the K-ras gene at codon 12 is thought to be an early genetic event in the multistep pathogenesis of pancreatic cancer. Since the risk of pancreatic cancer is significantly elevated in subjects with chronic pancreatitis, the aim of the present study was to determine the frequency of K-ras mutations in chronic pancreatitis., Methods: Pancreatic DNA from intraoperatively resected tissues of 60 patients with chronic pancreatitis and 11 patients with histologically confirmed pancreatic carcinoma was evaluated by PCR amplification and restriction fragment length polymorphism analysis., Results: In none of the 60 samples of chronic pancreatitis could K-ras mutations be identified using two independent PCR assays. In 5 of 11 patients with pancreatic carcinoma, K-ras mutations in codon 12 were detected., Conclusion: These data indicate that K-ras mutations are rare events in chronic pancreatitis. Alternatively, it is possible that the time span between the occurrence of K-ras mutations and malignant transformation is rather short.