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Query: UMLS:C0149521 (chronic pancreatitis)
 7,199 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic pancreatitis (CP) is characterised by pancreatic inflammation and fibrosis leading eventually to destruction of pancreatic parenchyma and loss of exocrine and endocrine function. A model of interactions between environmental triggers of pancreatic inflammation and disease susceptibility or modifying genes (including PRSS1, SPINK1 and CFTR) provides a framework within which to understand disease pathogenesis. Early in the disease, when fibrosis is mild and pancreatic damage limited, it is difficult to distinguish CP from recurrent acute pancreatitis (RAP) although it is likely these represent opposite ends of a spectrum of disease with a common aetiology in which CP represents either a later disease stage or disease in individuals predisposed to generate a chronic fibrogenic inflammatory response. Pain is a dominant feature resulting in part from neuroimmune interactions within the pancreas. Diagnosis at an early stage of disease is challenging, though in later stages is dependent upon the demonstration of pancreatic fibrosis and duct ectasia using one or more imaging modalities including transabdominal and endoscopic ultrasound, CT and MRCP or ERCP. Current treatments are largely supportive and reactive. The challenge for pediatricians is to achieve diagnosis at an early stage of the disease and to develop treatments that can alter its natural history.
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PMID:Chronic pancreatitis. 1709 Sep 3

Pancreatic stellate cells (PSCs) are the main source of extracellular matrix proteins in pancreatic fibrosis, a pathological feature of chronic pancreatitis and pancreatic cancer. Interferon-gamma (IFN-gamma) is an antifibrotic cytokine, but how precisely it exerts its effects on PSCs is largely unknown. Here, we have focussed on the role of STAT1 as well as target genes of IFN-gamma signalling. Our data indicate that IFN-gamma regulates the expression of two autocrine mediators of PSC activation, connective tissue growth factor and endothelin-1, in a transforming growth factor-beta1-antagonistic manner. STAT1 overexpression under the control of a tetracycline-dependent promoter revealed a close correlation between STAT1 expression and activation, the biological effects of IFN-gamma (growth inhibition, induction of apoptosis), and target gene expression. Our data further support the hypothesis that IFN-gamma interferes with stellate cell activation in the pancreas and suggest activated STAT1 as an inductor of a quiescent PSC phenotype.
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PMID:Inhibitory effects of interferon-gamma on activation of rat pancreatic stellate cells are mediated by STAT1 and involve down-regulation of CTGF expression. 1711 88

Chronic pancreatitis, an irreversible inflammatory disease of the pancreas, is characterized by chronic inflammatory cell infiltration, acinar cell degeneration, and development of fibrosis, which lead to impairment of pancreatic exocrine and endocrine function. Despite marked progress in diagnostic tools and, especially, imaging methods, no consensus has been reached on nomenclature in diagnosis of chronic pancreatitis. A major problem is that no reliable diagnostic test exists for early-stage chronic pancreatitis. The identification of the chemokine system, however, has elucidated the molecular mechanisms of the inflammation contributing to the development of fibrosis in the progression of chronic pancreatitis. Inflammatory chemokines are obviously associated with the chemoattraction of leukocytes in early-stage chronic pancreatitis. Migration of monocytes into the pancreas is one of the earliest events in the formation of pancreatic fibrosis. In particular, monocyte chemoattractant protein-1 (MCP-1) is considered to be a prefibrogenic factor in the progression of chronic pancreatitis. Lately, fractalkine/CX3CL1 is reported to be a membrane-spanning adhesion molecule that can be cleaved from the cell surface to produce a soluble chemoattractant. Our preliminary study showed that serum soluble fractalkine did not correlate with MCP-1 or transforming growth factor beta1 and increased in patients with early-stage chronic pancreatitis. Furthermore, serum soluble fractalkine did not correlate with pancreatic-specific enzymes, such as pancreatic amylase and lipase, and N-benzoyl-L-tyrosyl-p-aminobenzoic acid test results. Therefore, measurement of soluble fractalkine in human serum may be useful as a diagnostic marker of early-stage chronic pancreatitis, and should be considered in future studies, including detailed investigations of soluble fractalkine in patients with chronic pancreatitis.
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PMID:Can measurement of chemokines become useful biological and functional markers of early-stage chronic pancreatitis? 1723 32

Chronic pancreatitis (CP) is characterized by progressive pancreatic damage that eventually results in significant impairment of exocrine as well as endocrine functions of the gland. In Western societies, the commonest association of chronic pancreatitis is alcohol abuse. Our understanding of the pathogenesis of CP has improved in recent years, though important advances that have been made with respect to delineating the mechanisms responsible for the development of pancreatic fibrosis (a constant feature of CP) following repeated acute attacks of pancreatic necroinflammation (the necrosis-fibrosis concept). The pancreatic stellate cells (PSCs) are now established as key cells in fibrogenesis, particularly when activated either directly by toxic factors associated with pancreatitis (such as ethanol, its metabolites or oxidant stress) or by cytokines released during pancreatic necroinflammation. In recent years, research effort has also focused on the genetic abnormalities that may predispose to CP. Genes regulating trypsinogen activation/inactivation and cystic fibrosis transmembrane conductance regulator (CFTR) function have received particular attention. Mutations in these genes are now increasingly recognized for their potential 'disease modifier' role in distinct forms of CP including alcoholic, tropical, and idiopathic pancreatitis. Treatment of uncomplicated CP is usually conservative with the major aim being to effectively alleviate pain, maldigestion and diabetes, and consequently, to improve the patient's quality of life. Surgical and endoscopic interventions are reserved for complications such as pseudocysts, abscess, and malignancy.
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PMID:Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. 1763 Nov 65

Human chronic pancreatitis is characterized by irreversible fibrosis, whereas pancreatic fibrosis in animal models is reversible. In this study, we compare the development of pancreatic fibrosis in the dibutyltin dichloride (DBTC) model, WBN/Kob rats and bile duct-ligated (BDL) rats. DBTC (8 mg/kg) was administered to LEW rats, and the pancreas was histopathologically investigated sequentially. Male and female WBN/Kob rats aged 4, 6 and 8 months were also examined. BDL rats were prepared by ligation of the bile duct at the duodenal portion and sacrificed at 3 or 7 days after ligation. Fibrosis in the DBTC model peaked after 1 week and was limited to the areas around the pancreatic ducts after 2 weeks, and was composed of both type I and type III collagen. In contrast, fibrosis in male WBN/Kob rats peaked at age 4 months, expanded into intralobular area, and was composed of type III collagen. It exhibited almost no type I collagen and a marked tendency to regress. Pancreatic fibrosis in BDL rats was somewhat difficult to induce and required increased stimulation. This suggests that fibrosis in human biliary pancreatitis may gradually form based on weak, continuous stimulation. We conclude that type I collagen may be involved in the progression of irreversible fibrosis. The imbalance between synthesis and degradation of extracellular matrix molecules or degree of stimulation over a certain period may lead to pancreatic fibrosis. Gene expressions of prolyl hydroxylase and tissue inhibitors of matrix metalloproteinase-2 were elevated.
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PMID:Role of fibrosis-related genes and pancreatic duct obstruction in rat pancreatitis models: implications for chronic pancreatitis. 1761 39

Local tissue pressure is higher in chronic pancreatitis than in the normal pancreas. We reported recently that pressure application induces synthesis of extracellular matrix (ECM) and cytokines in pancreatic stellate cells (PSCs) and that epigallocatechin gallate (EGCG), a potent antioxidant, inhibits the transformation of PSCs from quiescent to activated phenotype and ethanol-induced synthesis of ECM and cytokines in PSCs. These results suggest that oxidative stress and reactive oxygen species (ROS) are important in PSC activation. The aim of this study was to clarify the effects of ROS on activation and functions of pressure-stimulated PSCs. We used freshly isolated rat PSCs and culture-activated PSCs. Pressure was applied on rat cultured PSCs by adding compressed helium gas into a pressure-loading apparatus. PSCs were cultured with or without antioxidants (EGCG and N-acetyl cysteine) under normal or elevated pressure. Externally applied high pressure (80 mmHg) resulted in a gradual decrease of superoxide dismutase activity in PSCs and increased intracellular ROS generation as early as 30 s, reaching a peak level at 1 h. Antioxidants significantly inhibited ROS generation. Pressure increased the expression levels of alpha-smooth muscle actin, alpha(1)(I)-procollagen, and TGF-beta1 in PSCs. EGCG suppressed these alterations, abolished pressure-induced phosphorylation of p38 MAPK, and suppressed pressure-induced PSC transformation to activated phenotype. Our results indicated that ROS is a key player in pressure-induced PSC activation and ECM synthesis. Antioxidants could be potentially effective against the development of pancreatic fibrosis in patients with chronic pancreatitis.
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PMID:Externally applied pressure activates pancreatic stellate cells through the generation of intracellular reactive oxygen species. 1776 38

Chronic pancreatitis (CP) still remains a challenging clinical problem with many controversial issues regarding pathogenesis, outcome, and treatment. The disease comprises a spectrum of disorders that culminate as a final step in the destruction of the pancreas. Complex interaction does exist between genetic, environmental and immunologic factors leading to development of the disease. Multiple risk factors interact in a multiple-step model; the pancreatic injury may occur through different mechanisms with transition between an acute pancreatitis condition to recurrent pancreatitis and, finally, to CP. Most patients have multiple risk factors and the overall risk is a product of all risk factors in additive or multiplicative fashion. Susceptibility to develop CP in alcoholics depends on the expression of single gene mutation or is derived from complex genetic polymorphism; in addition, smoking habit can influence the risk of pancreatic calcifications and severity in alcoholic and idiopathic CP. Alteration of the immune response induced by gene mutations and/or environmental factors represents the main determinant of pancreatic fibrosis, the end-stage histologic feature from all CP etiologies.
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PMID:Risk factors of chronic pancreatitis. 1782 58

Alcoholic intake has increased in society in recent years. gamma-GTP is used as a marker of liver damage by alcohol intake, but there is no reliable marker of pancreatic fibrosis. We used animal experiments and clinical data to identify a new reliable marker of early-stage pancreatic fibrosis. Pancreatic fibrosis is induced by intra-peritoneal injection of diethyldithiocarbamate. Pancreas tissue was extracted and measured. Human pure pancreatic juice was collected by endoscopic procedures. Prolyl hydroxylase in pancreas tissue is increased in the early stage of pancreatic fibrosis. Secretion of matrix metalloproteinase from pancreatic stellate cells is increased by diethyldithiocarbamate stimulation. Pancreatic stellate cells, prolyl hydroxylase and a tissue inhibitor of metalloproteinase in human pure pancreatic juice is increased in heavy alcohol drinkers and normalized in former alcohol drinkers. Active matrix metalloproteinase 2 is detected in pure pancreatic juice of chronic pancreatitis patients. Treatment with oral camostat increases pancreatic secretory trypsin inhibitor in chronic pancreatitis patients. Experimental and clinical data indicated that matrix metalloproteinase 2 and prolyl hydroxylase are candidates as markers of early-stage pancreatic fibrosis. Clinical data showed that tissue inhibitor of metalloproteinase and pancreatic secretory trypsin inhibitor in pure pancreatic juice had potential as markers of early-stage pancreatic fibrosis.
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PMID:[Fibrosis markers in heavy alcohol drinkers]. 1788 97

Activated pancreatic stellate cells (PSCs) play an important role in pancreatic fibrosis and inflammation, where oxidative stress is implicated in the pathogenesis. NADPH oxidase might be a source of reactive oxygen species (ROS) in the injured pancreas. This study aimed to clarify the expression and regulation of cell functions by NADPH oxidase in PSCs. PSCs were isolated from rat and human pancreas tissues. Expression of NADPH oxidase was assessed by reverse transcription-PCR and immunostaining. Intracellular ROS production was assessed using 2',7'-dichlorofluorescin diacetate. The effects of diphenylene iodonium (DPI) and apocynin, inhibitors of NADPH oxidase, on key parameters of PSC activation were evaluated in vitro. In vivo, DPI (at 1 mg.kg body wt(-1).day(-1)) was administered in drinking water to 10-wk-old male Wistar Bonn/Kobori rats for 10 wk and to rats with chronic pancreatitis induced by dibutyltin dichloride (DBTC). PSCs expressed key components of NADPH oxidase (p22(phox), p47(phox), NOX1, gp91(phox)/NOX2, NOX4, and NOX activator 1). PDGF-BB, IL-1beta, and angiotensin II induced ROS production, which was abolished by DPI and apocynin. DPI inhibited PDGF-induced proliferation, IL-1beta-induced chemokine production, and expression of alpha-smooth muscle actin and collagen. DPI inhibited transformation of freshly isolated cells to a myofibroblast-like phenotype. In addition, DPI inhibited the development of pancreatic fibrosis in Wistar Bonn/Kobori rats and in rats with DBTC-induced chronic pancreatitis. In conclusion, PSCs express NADPH oxidase to generate ROS, which mediates key cell functions and activation of PSCs. NADPH oxidase might be a potential target for the treatment of pancreatic fibrosis.
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PMID:NADPH oxidase plays a crucial role in the activation of pancreatic stellate cells. 1796 58

Chronic pancreatitis and pancreatic cancer are characterised by a progressive fibrosis. Accumulation of extracellular matrix not only accompanies both diseases but is directly involved in their progression, suggesting inhibition of fibrogenesis as a potential therapeutic strategy. Pancreatic stellate cells (PSC) are the main extracellular matrix-producing cell type in the diseased pancreas. In response to pro-fibrogenic mediators including cytokines and ethanol metabolites, PSC undergo phenotypic changes termed activation, resulting in the exhibition of a myofibroblast-like phenotype. In the perpetuation of PSC activation, autocrine loops of mediators such as transforming growth factor beta play an important role. Most recently signal transduction pathways in PSC that are associated with the process of activation were characterised, facilitating identification of potential intracellular targets for an anti-fibrotic therapy. While some putative inhibitors of fibrogenesis have been tested in animal models of pancreatic fibrosis for their in vivo efficiency, clinical studies still remain to be performed.
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PMID:Crucial role of fibrogenesis in pancreatic diseases. 1820 10


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