Models of Acute and Chronic Pancreatitis
TL;DR: Animal models of acute and chronic pancreatitis have been created to examine mechanisms of pathogenesis, test therapeutic interventions, and study the influence of inflammation on the development of pancreatic cancer.
About: This article is published in Gastroenterology.The article was published on 2013-05-01. It has received 313 citations till now. The article focuses on the topics: Pancreatitis & Autoimmune pancreatitis.
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TL;DR: It is shown that pharmacologic inhibition of IL-4/IL-13 in human ex-vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis, and identifies a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage alternative activation.
Abstract: Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis (AP), we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on interleukin (IL)-4 and IL-13 signalling, and we show that mice lacking IL-4Rα, myeloid-specific IL-4Rα and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage-alternative activation. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.
244 citations
TL;DR: In different animal models, a central role is found for mitochondrial dysfunction, and for impaired autophagy as its principal downstream effector, in development of AP, a model of severe AP the pathogenesis of which has remained unknown.
197 citations
Cites background from "Models of Acute and Chronic Pancrea..."
...Because of limited access to human tissue, the knowledge on molecular/cellular pathways initiating and driving pancreatitis comes mainly from experimental models that appear to reproduce key responses of human disease.(3) There are significant gaps in our understanding of these pathways, in particular the role of mitochondrial dysfunction....
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TL;DR: Cytosolic calcium overload, mediated via ORAI1, contributes to the pathogenesis of acute pancreatitis.
155 citations
TL;DR: The NFκB signaling pathway is a critical determinant of pancreatic inflammation and metaplasia, whereas a number of developmental signals and transcription factors are devoted to promoting acinar redifferentiation after injury.
Abstract: Pancreatitis is caused by inflammatory injury to the exocrine pancreas, from which both humans and animal models appear to recover via regeneration of digestive enzyme-producing acinar cells. This regenerative process involves transient phases of inflammation, metaplasia, and redifferentiation, driven by cell-cell interactions between acinar cells, leukocytes, and resident fibroblasts. The NFκB signaling pathway is a critical determinant of pancreatic inflammation and metaplasia, whereas a number of developmental signals and transcription factors are devoted to promoting acinar redifferentiation after injury. Imbalances between these proinflammatory and prodifferentiation pathways contribute to chronic pancreatitis, characterized by persistent inflammation, fibrosis, and acinar dedifferentiation. Loss of acinar cell differentiation also drives pancreatic cancer initiation, providing a mechanistic link between pancreatitis and cancer risk. Unraveling the molecular bases of exocrine regeneration may identify new therapeutic targets for treatment and prevention of both of these deadly diseases.
134 citations
TL;DR: Dietary antioxidants, especially in combination with palm oil-derived fatty acids, blocked progression to CP and pancreatic acinar atrophy and might be used to identify therapeutic targets for CP.
118 citations
References
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TL;DR: X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site, and that loss of this cleavage site would permit autodigestion resulting in pancreatitis.
Abstract: Hereditary pancreatitis (HP) is a rare, early-onset genetic disorder characterized by epigastric pain and often more serious complications. We now report that an Arg–His substitution at residue 117 of the cationic trypsinogen gene is associated with the HP phenotype. This mutation was observed in all HP affected individuals and obligate carriers from five kindreds, but not in individuals who married into the families nor in 140 unrelated individuals. X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site. Cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis.
1,471 citations
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TL;DR: There is a wide spectrum of disease from mild (80%), where patients recover within a few days, to severe (20%) with prolonged hospital stay, the need for critical care support, and a 15-20% risk of death.
Abstract: Acute pancreatitis is inflammation of the pancreas; it is sometimes associated with a systemic inflammatory response that can impair the function of other organs or systems. The inflammation may settle spontaneously or may progress to necrosis of the pancreas or surrounding fatty tissue. The distant organ or system dysfunction may resolve or may progress to organ failure. Thus there is a wide spectrum of disease from mild (80%), where patients recover within a few days, to severe (20%) with prolonged hospital stay, the need for critical care support, and a 15-20% risk of death. If patients have organ failure during the first week in hospital, it is usually already present on the first day in hospital. This early organ failure may resolve in response to treatment. The diagnosis of severe acute pancreatitis depends on the presence of persistent organ failure (>48 hours) either during the first week or at a later stage, and also on the presence of local complications (usually apparent after the first week).
1,399 citations
TL;DR: The categorization of AIP into types 1 and 2 should be helpful for further clarification of the clinical features, pathogenesis, and natural history of these diseases.
Abstract: Objectives:To achieve the goal of developing international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP).Methods:An international panel of experts met during the 14th Congress of the International Association of Pancreatology held in Fukuoka, Japan, from July 11 through 13,
1,232 citations
TL;DR: Findings suggest a special role for translational control in protecting secretory cells from ER stress in diabetes mellitus and exocrine pancreatic insufficiency.
1,195 citations
TL;DR: It is reported that selective expression of an endogenous K-Ras(G12V) oncogene in embryonic cells of acinar/centroacinar lineage results in pancreatic intraepithelial neoplasias (PanINs) and invasive PDA, suggesting that PDA originates by differentiation of acINs or their precursors into ductal-like cells.
1,074 citations