Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149521 (chronic pancreatitis)
 7,199 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that troglitazone inhibits proinflammatory cytokine production in chronic pancreatitis. In the present study, we show that troglitazone prevents the progression of chronic pancreatitis by inhibiting the proliferation of pancreatic stellate cells (PSCs) via a PPARgamma-independent mechanism. WBN/Kob rats with spontaneous chronic pancreatitis were fed troglitazone-containing rat chow for 3 or 6 months. Pancreatic fibrosis and expression of alpha-SMA were markedly attenuated by troglitazone. Rat PSCs expressed a higher level of PPARgamma1 mRNA than of PPARgamma2 mRNA. PSCs were transiently cotransfected with a dominant negative mutant PPARgamma1 and a PPAR-driven reporter gene. Troglitazone increased reporter activity and the mutant receptor abrogated wild-type receptor activity in a dose-dependent manner. Troglitazone inhibited cell proliferation by blocking cell-cycle progression beyond the G1 phase. These effects were observed in mutant receptor-transfected cells as well as cells transfected with the control vector. The effect of troglitazone on alpha1(I) procollagen mRNA and MCP-1 mRNA was unaffected by inhibition of endogenous PPARgamma1 receptor activity. These results suggest that troglitazone may serve as novel therapeutic agent for the treatment of chronic pancreatitis. The antifibrotic effect of troglitazone appears to be mediated, in part, via a PPARgamma-independent mechanism.
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PMID:Troglitazone inhibits the progression of chronic pancreatitis and the profibrogenic activity of pancreatic stellate cells via a PPARgamma-independent mechanism. 1521 Nov 14

Chronic pancreatitis is a disease whose pathomechanism has not yet been fully explained. Some progress has been made in recent years, however, mainly due to the identification and description of pancreatic stellate cells (PSCs). In 1998 Bachem observed that the vitamin A-storing cells present in the pancreas, when subjected to activation, transformed into myofibroblasts capable of producing collagens I and II and fibronectin, which contributes to fibrosis in chronic pancreatitis. The development of chronic pancreatitis also seems likely to be affected by the cytokines, among other things, as a result of repeated PSC activation. The current literature provides more and more data suggesting that cytokines play an important role in the regulation of inflammation and fibrosis in CP. A major role in the pathogenesis of chronic pancreatitis is attributed to interleukin 1, 6, 10, tumour necrosis factor a (TNF-a) and transforming growth factor b1 (TGF-b1). All these factors have pro- and anti-inflammatory effects, and act simultaneously. Their effects on PSCs can be synergistic, antagonistic or complementary. Further comprehensive studies are needed to determine precisely the role of the individual cytokines and PSCs, as well as their relationships. However, the present state of our knowledge suggests that repeated episodes of AP and thus exposure to increased cytokine secretion may contribute to persistent chronic activation of PSCs, resulting in pancreatic fibrosis and chronic pancreatitis.
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PMID:The role of pancreatic stellate cells and cytokines in the development of chronic pancreatitis. 1523 19

Pancreatic stellate cells (PSCs) play a central role in development of pancreatic fibrosis. In chronic pancreatitis, pancreatic tissue pressure is higher than that of the normal pancreas. We here evaluate the effects of pressure on the activation of rat PSCs. PSCs were isolated from the pancreas of Wistar rat using collagenase digestion and centrifugation with Nycodenz gradient. Pressure was applied to cultured rat PSCs by adding compressed helium gas into the pressure-loading apparatus to raise the internal pressure. Cell proliferation rate was assessed by 5-bromo-2'-deoxyuridine (BrdU) incorporation. MAPK protein levels and alpha-smooth muscle actin (alpha-SMA) expression were evaluated by Western blot analysis. Concentration of activated transforming growth factor-beta1 (TGF-beta1) secreted from PSCs into culture medium was determined by ELISA. Collagen type I mRNA expression and collagen secretion were assessed by quantitative PCR and Sirius red dye binding assay, respectively. Application of pressure significantly increased BrdU incorporation and alpha-SMA expression. In addition, pressure rapidly increased the phosphorylation of p44/42 and p38 MAPK. Treatment of PSCs with an MEK inhibitor and p38 MAPK inhibitor suppressed pressure-induced cell proliferation and alpha-SMA expression, respectively. Moreover, pressure significantly promoted activated TGF-beta1 secretion, collagen type I mRNA expression, and collagen secretion. Our results demonstrate that pressure itself activates rat PSCs and suggest that increased pancreatic tissue pressure may accelerate the development of pancreatic fibrosis in chronic pancreatitis.
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PMID:Pressure activates rat pancreatic stellate cells. 1531 86

Until now, no specific therapies are available to inhibit pancreatic fibrosis, a constant pathological feature of chronic pancreatitis and pancreatic cancer. One major reason is the incomplete knowledge of the molecular principles underlying fibrogenesis in the pancreas. In the past few years, evidence has been accumulated that activated pancreatic stellate cells (PSCs) are the predominant source of extracellular matrix (ECM) proteins in the diseased organ. PSCs are vitamin A-storing, fibroblast-like cells with close morphological and biochemical similarities to hepatic stellate cells (also known as Ito-cells). In response to profibrogenic mediators such as various cytokines, PSCs undergo an activation process that involves proliferation, exhibition of a myofibroblastic phenotype and enhanced production of ECM proteins. The intracellular mediators of activation signals, and their antagonists, are only partially known so far. Recent data suggest an important role of enzymes of the mitogen-activated protein kinase family in PSC activation. On the other hand, ligands of the nuclear receptor PPARgamma (peroxisome proliferator-activated receptor gamma) stimulate maintenance of a quiescent PSC phenotype. In the future, targeting regulators of the PSC activation process might become a promising approach for the treatment of pancreatic fibrosis.
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PMID:Molecular regulation of pancreatic stellate cell function. 1546 5

Camostat mesilate (CM), an oral protease inhibitor, has been used clinically for the treatment of chronic pancreatitis in Japan. However, the mechanism by which it operates has not been fully understood. Our aim was to evaluate the therapeutic efficacy of CM in the experimental pancreatic fibrosis model induced by dibutyltin dichloride (DBTC), and we also determined the effect of CM on isolated monocytes and panceatic stellate cells (PSCs). In vivo, chronic pancreatitis was induced in male Lewis rats by single administration of 7 mg/kg DBTC and a special diet containing 1 mg/g CM was fed to the DBTC+CM-treated group from day 7, while the DBTC-treated group rats were fed a standard diet. At days 0, 7, 14 and 28, the severity of pancreatitis and fibrosis was examined histologically and enzymologically in both groups. In vitro, monocytes were isolated from the spleen of a Lewis rat, and activated with lipopolysaccharide stimulation. Thereafter, the effect of CM on monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) production from monocytes was examined. Subsequently, cultured rat PSCs were exposed to CM and tested to see whether their proliferation, MCP-1 production and procollagen alpha1 messenger RNA expression was influenced by CM. In vivo, the oral administration of CM inhibited inflammation, cytokines expression and fibrosis in the pancreas. The in vitro study revealed that CM inhibited both MCP-1 and TNF-alpha production from monocytes, and proliferation and MCP-1 production from PSCs. However, procollagen alpha1 expression in PSCs was not influenced by CM. These results suggest that CM attenuated DBTC-induced rat pancreatic fibrosis via inhibition of monocytes and PSCs activity.
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PMID:Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity. 1553 8

Alcohol consumption is a risk factor for chronic pancreatitis (CP), but the mechanism in humans remains obscure because prolonged alcohol consumption in most humans and animal models fails to produce alcoholic chronic pancreatitis (ACP). We hypothesize that the process leading to ACP is triggered by a sentinel acute pancreatitis (AP) event; this event causes recruitment of inflammatory cells, which initiates fibrosis driven by the anti-inflammatory response to recurrent AP and/or chronic oxidative stress. The aim was to determine whether chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in the rat. Wistar male rats were pair-fed control (C) or 5% ethanol (E) Lieber-DeCarli liquid diets. Animals were studied without pancreatitis (P0), with cerulein pancreatitis induced once (P1), or with cerulein-induced pancreatitis weekly for 3 weeks (P3). AP markers, inflammation, and fibrosis were measured histologically, by gene expression profiling and protein expression. Macrophage infiltration was reduced in EP0 versus CP0 rats, but the pattern was reversed after AP. Microabscess, severe necrosis, and early calcification were only induced in the EP3 rats. Fibrosis was significantly induced in the EP3 rats versus EP1, CP1, and CP3 by histology, hydroxyproline content, and mRNA expression for collagen alpha1(1) and procollagen alpha2(1). Proinflammatory cytokine mRNAs were up-regulated shortly after induction of AP, while the anti-inflammatory cytokines (interleukin-10 and transforming growth factor-beta) were strongly up-regulated later and in parallel with fibrogenesis, especially in the EP3 rats. Pancreatic fibrosis develops after repeated episodes of AP and is potentiated by alcohol. Expression of fibrosis-associated genes was associated with expression of anti-inflammatory cytokines in alcohol-fed rats.
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PMID:Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in rats. 1563 3

Autoimmune chronic pancreatitis (AICP) is a clinically attractive entity because of its dramatic response to steroid therapy. Reported cases of AICP until now have focused on mainly clinical, radiologic, and laboratory features with steroid therapy. There are, however, few reports that demonstrate histologic recovery, especially regression of pancreatic fibrosis in patients with AICP. Fibrosis in chronic pancreatitis is generally believed to be irreversible. Our observation of reversibility of pancreatic fibrosis is, therefore, noteworthy. We illustrate this with 2 cases of AICP in which pancreatic fibrosis as well as inflammatory infiltration regressed after a short course of oral steroid therapy.
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PMID:Regression of pancreatic fibrosis after steroid therapy in patients with autoimmune chronic pancreatitis. 1563 4

The pathophysiology of pain in chronic pancreatitis (CP) is incompletely understood. Several hypotheses have been advanced, including pancreatic and extrapancreatic causes. The existence of different hypotheses to explain the genesis of pain in CP also reflects the different therapeutic approaches to pain in these patients. Increased intraductal pressure as a result of single or multiple strictures and/or calculi is believed to be a common cause of pain in CP patients with a dilated main pancreatic duct. Other suggested causes include pancreatic fibrosis, interstitial hypertension and pancreatic ischemia. Additionally, extrapancreatic causes like duodenal and common bile duct stenosis with scarring due to pancreatic inflammation are suggested as factors causing pain in CP. The 'neurogenic inflammation' hypothesis is a fascinating theory which is supported by different studies. Immunohistological reports have shown that the amount of neurotransmitters, such as substance P and its receptor, calcitonin gene-related peptide and other neurotransmitters, are increased in afferent pancreatic nerves and a correlation between pain and immune cell infiltration of the nerves has been reported in CP. In this review we will discuss the different pain hypotheses and will present the perspective that neuroimmune interaction is an important factor for pain generation in CP.
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PMID:Pathogenesis of pain in chronic pancreatitis. 1575 9

Pancreatic fibrosis, a characteristic histopathological feature of chronic pancreatitis, is no longer considered an epiphenomenon of chronic injury, but an active process that may be reversible in the early stages. The identification and characterization of pancreatic stellate cells (PSCs) in recent years has had a significant impact on research into pancreatic fibrogenesis. Accumulating evidence from both in vivo studies (using human pancreatic sections and experimental models of pancreatic fibrosis) and in vitro studies (using cultured pancreatic stellate cells) indicates a key role for activated PSCs in the fibrotic process. These cells are now known to be activated by ethanol and its metabolites and by several factors that are upregulated during pancreatic injury including growth factors, cytokines and oxidant stress. Based on this knowledge, potential antifibrotic strategies such as antioxidants and cytokine inhibition have been assessed in experimental models. Studies are also underway to characterise the signaling pathways/molecules responsible for mediating PSC activation, in order to identify potential therapeutic targets for the inhibition of PSC activation, thereby preventing or reversing the development of pancreatic fibrosis.
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PMID:Mechanisms of pancreatic fibrosis. 1575 10

Pancreatic stellate cells (PSCs) play a key role in the development of pancreatic fibrosis, a pathological feature of chronic pancreatitis and pancreatic cancer. Here, we show that activation of rat PSCs in vitro is associated with increased expression of galectin-1 (gal-1) and that gal-1 modulates PSC function. Expression of the lectin was stimulated by fetal calf serum and platelet-derived growth factor. PSCs exposed to exogenous gal-1 proliferated at a higher rate and synthesised more collagen than controls. Gal-1-dependent collagen synthesis was blocked by lactose but not by cellobiose, suggesting that gal-1 acts on PSCs through targeting beta-galactoside-containing glycoconjugates. Analysis of gal-1 signalling in PSCs revealed an activation of the extracellular signal-regulated kinases 1 and 2 and enhanced DNA binding of AP-1 transcription factors. Together, our data implicate gal-1 in PSC activation and suggest further studies to analyse the role of endogenous lectins in the development of pancreatic fibrosis in vivo.
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PMID:Galectin-1 is an inductor of pancreatic stellate cell activation. 1603 98


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