Advances in Acute and Chronic Pancreatitis: From Development to Inflammation and Repair

Magliano, Marina Pasca di; Forsmark, Christopher E.; Freedman, Steven D.; Hebrok, Matthias; Pasricha, Pankaj J.; Saluja, Ashok K.; Stanger, Ben Z.; Holt, Jane; Serrano, José; James, Stephen P.; Rustgi, Anil K.

doi:10.1053/j.gastro.2012.11.018

Cited by 16 publications

(8 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the increasing burden of this disease there remains no therapy directed to the molecular pathogenesis that has established efficacy in altering the natural history of this condition. An international panel of experts convened by the National Institutes of Health in Bethesda, MD, concluded in 2012 that despite improvement in our understanding of the mechanistic pathways underlying acute pancreatitis, there has been a lack of progress in development of new clinical therapies (3). In addition to lack of therapies, the field lacks a standardized quantitative system to measure disease activity at any given time during the course of acute pancreatitis.…”

Section: Introductionmentioning

confidence: 99%

Dynamic Measurement of Disease Activity in Acute Pancreatitis: The Pancreatitis Activity Scoring System

Batech

Quezada

et al. 2017

American Journal of Gastroenterology

View full text Add to dashboard Cite

OBJECTIVES Acute pancreatitis has a highly variable course. Currently there is no widely accepted method to measure disease activity in patients hospitalized for acute pancreatitis. We aimed to develop a clinical activity index that incorporates routine clinical parameters to assist in the measurement, study, and management of acute pancreatitis. METHODS We used the UCLA/RAND appropriateness method to identify items for inclusion in the disease activity instrument. We conducted a systematic literature review followed by two sets of iterative modified Delphi meetings including a panel of international experts between November 2014 and November 2015. The final instrument was then applied to patient data obtained from five separate study cohorts across Southern California to assess profiles of disease activity. RESULTS From a list of 35 items comprising 6 domains, we identified 5 parameters for inclusion in the final weighted clinical activity scoring system: organ failure, systemic inflammatory response syndrome, abdominal pain, requirement for opiates and ability to tolerate oral intake. We applied the weighted scoring system across the 5 study cohorts comprising 3,123 patients. We identified several distinct patterns of disease activity: (i) overall there was an elevated score at baseline relative to discharge across all study cohorts, (ii) there were distinct patterns of disease activity related to duration of illness as well as (iii) early and persistent elevation of disease activity among patients with severe acute pancreatitis defined as persistent organ failure. CONCLUSIONS We present the development and initial validation of a clinical activity score for real-time assessment of disease activity in patients with acute pancreatitis.

show abstract

Section: Introductionmentioning

confidence: 99%

Dynamic Measurement of Disease Activity in Acute Pancreatitis: The Pancreatitis Activity Scoring System

Batech

Quezada

et al. 2017

American Journal of Gastroenterology

View full text Add to dashboard Cite

show abstract

“…Chronic pancreatitis in the United States results in more than 122,000 outpatient visits and more than 56,000 hospitalizations each year (2). Many patients with chronic pancreatitis develop insulinopenia, glucose intolerance, insulin resistance, and eventually diabetes (2), largely as a result of the intimate proximity of the endocrine pancreas to the exocrine pancreas (3). Moreover, patients with chronic pancreatitis often develop a fibrotic pancreas with a reduced β-cell mass and have a 15- to 16-fold increased risk for pancreatic cancer (4).…”

Section: Introductionmentioning

confidence: 99%

SMAD3/Stat3 Signaling Mediates β-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis–Related Diabetes

et al. 2017

View full text Add to dashboard Cite

Many patients with chronic pancreatitis develop diabetes (chronic pancreatitis–related diabetes [CPRD]) through an undetermined mechanism. Here we used long-term partial pancreatic duct ligation (PDL) as a model to study CPRD. We found that long-term PDL induced significant β-cell dedifferentiation, followed by a time-dependent decrease in functional β-cell mass—all specifically in the ligated tail portion of the pancreas (PDL-tail). High levels of transforming growth factor β1 (TGFβ1) were detected in the PDL-tail and were mainly produced by M2 macrophages at the early stage and by activated myofibroblasts at the later stage. Loss of β-cell mass was then found to result from TGFβ1-triggered epithelial-mesenchymal transition (EMT) by β-cells, rather than resulting directly from β-cell apoptosis. Mechanistically, TGFβ1-treated β-cells activated expression of the EMT regulator gene Snail in a SMAD3/Stat3-dependent manner. Moreover, forced expression of forkhead box protein O1 (FoxO1), an antagonist for activated Stat3, specifically in β-cells ameliorated β-cell EMT and β-cell loss and prevented the onset of diabetes in mice undergoing PDL. Together, our data suggest that chronic pancreatitis may trigger TGFβ1-mediated β-cell EMT to lead to CPRD, which could substantially be prevented by sustained expression of FoxO1 in β-cells.

show abstract

“…The disease initially presents as an acute attack characterized by abdominal pain, nausea and/or vomiting. Repeated bouts of acute pancreatitis (AP) produce a persistent inflammatory response that can rapidly progress to chronic disease characterized by fibrosis, with long-term consequences including increased risk of diabetes or pancreatic cancer [2]. …”

Section: Introductionmentioning

confidence: 99%

The MET Receptor Tyrosine Kinase Confers Repair of Murine Pancreatic Acinar Cells following Acute and Chronic Injury

et al. 2016

View full text Add to dashboard Cite

Acinar cells represent the primary target in necroinflammatory diseases of the pancreas, including pancreatitis. The signaling pathways guiding acinar cell repair and regeneration following injury remain poorly understood. The purpose of this study was to determine the importance of Hepatocyte Growth Factor Receptor/MET signaling as an intrinsic repair mechanism for acinar cells following acute damage and chronic alcohol-associated injury. Here, we generated mice with targeted deletion of MET in adult acinar cells (MET-/-). Acute and repetitive pancreatic injury was induced in MET-/- and control mice with cerulein, and chronic injury by feeding mice Lieber-DeCarli diets containing alcohol with or without enhancement of repetitive pancreatic injury. We examined the exocrine pancreas of these mice histologically for acinar death, edema, inflammation and collagen deposition and changes in the transcriptional program. We show that MET expression is relatively low in normal adult pancreas. However, MET levels were elevated in ductal and acinar cells in human pancreatitis specimens, consistent with a role for MET in an adaptive repair mechanism. We report that genetic deletion of MET in adult murine acinar cells was linked to increased acinar cell death, chronic inflammation and delayed recovery (regeneration) of pancreatic exocrine tissue. Notably, increased pancreatic collagen deposition was detected in MET knockout mice following repetitive injury as well alcohol-associated injury. Finally, we identified specific alterations of the pancreatic transcriptome associated with MET signaling during injury, involved in tissue repair, inflammation and endoplasmic reticulum stress. Together, these data demonstrate the importance of MET signaling for acinar repair and regeneration, a novel finding that could attenuate the symptomology of pancreatic injury.

show abstract

Advances in Acute and Chronic Pancreatitis: From Development to Inflammation and Repair

Abstract: 2016-12-23T18:52:10

Cited by 16 publications

References 20 publications

Dynamic Measurement of Disease Activity in Acute Pancreatitis: The Pancreatitis Activity Scoring System

Dynamic Measurement of Disease Activity in Acute Pancreatitis: The Pancreatitis Activity Scoring System

SMAD3/Stat3 Signaling Mediates β-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis–Related Diabetes

The MET Receptor Tyrosine Kinase Confers Repair of Murine Pancreatic Acinar Cells following Acute and Chronic Injury

Contact Info

Product

Resources

About