Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is little information available regarding the role of inflammatory cells and cytokines in the pancreatic tissue during acute interstitial pancreatitis. The single intravenous application of dibutyltin dichloride (DBTC) induces a pancreatitis in rats with a dosage dependent course. We analyzed the infiltrating leukocytes and the cytokine expression profile in the experimental model of DBTC-initiated mild interstitial pancreatitis during a time course of 4 weeks. Macrophages dominated among the infiltrating inflammatory cells detected by immunohistochemistry. The expression of IL-1beta, IL-10, and TGFbeta1 was shown to be elevated 24 hours after onset of pancreatitis reaching a maximum during the first week. Positive immunostaining of IL-1beta, IL-10, or TGFbeta1 was not restricted to infiltrating leukocytes but was found to various degrees in pancreatic cells. Transcripts of collagen type 1 reached high levels in the first week, but were down regulated thereafter. There was no significant expression of IL-2, IL-2 receptor, IL-4, TNFalpha, or IFNgamma. Our data show that the experimental interstitial pancreatitis was characterized by macrophage infiltration accompanied by elevated cytokine expression that lasted longer than the visible morphologic lesions. These inflammatory processes might create the environment that makes the pancreas more susceptible to further damaging effects.
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PMID:Immunologic characterization of acute pancreatitis in rats induced by dibutyltin dichloride (DBTC). 1282 12

The incidence of clinically significant pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) ranges from 1-13.5%. It is more common after therapeutic procedures such as sphincterotomy or balloon dilatation of the sphincter, and diagnostic procedures such as biliary or pancreatic manometry. The severity of post-ERCP pancreatitis may vary from very mild to extremely severe disease with multiple organ failure and fatal outcome. Several factors including papillary oedema, injection of hyperosmolar contrast-material, introduction of previously activated enzymes during repeated cannulation, bacterial contamination and thermal injury from endoscopic sphincterotomy have been implicated as triggering factors that initiate the sequential cascade of pancreatic autodigestion and release of proinflammatory cytokines leading to acute pancreatitis. Recovery from post-ERCP pancreatitis is usually rapid when the injury is confined to the pancreas. However, systemic production of inflammatory mediators may lead to the development of more serious manifestations including multiorgan failure.A wide range of pharmacological agents has been tested in experimental and clinical trials, but the results have been largely disappointing. Several drugs are discussed in this review, but only somatostatin and gabexate (gabexate mesilate) have consistently shown a moderate beneficial effect. In clinical trials, both gabexate and somatostatin appear equally effective in reducing the incidence of pancreatitis by two-thirds compared with controls. However, both drugs need to be given by continuous infusion for about 12 hours and this makes them less cost-effective than conventional treatment. One potential strategy is to reserve these drugs for high-risk patients undergoing ERCP. Preliminary studies have shown encouraging results with nitroglycerin, antibacterials and heparin. However, these observations need to be corroborated in a rigorous fashion in large, randomised, double-blind, controlled trials. If these drugs are found to be effective in further trials, it may become cost-effective to use them routinely for the prevention of post-ERCP pancreatitis. Despite the theoretical benefits, interleukin-10 has not shown a consistent benefit in clinical trials. It is probable that other cytokine inhibitors or modulators may become available for future trials to prevent pancreatitis or more probably, to reduce the severity of pancreatitis. Further research also should focus on developing newer molecules or the use of a combination of currently available drugs to prevent pancreatitis in high-risk patients undergoing therapeutic ERCP procedures.
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PMID:Pharmacological prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis. 1292 86

The pathogenesis of pancreatic fibrosis, a characteristic feature of alcohol-induced chronic pancreatitis, has received increasing attention over the past few years, largely due to the identification and characterization of stellate cells in the pancreas. These cells are morphologically similar to hepatic stellate cells, the principal effector cells in liver fibrosis. The role of pancreatic stellate cells (PSCs) in alcoholic pancreatic fibrosis has been studied using 2 approaches: (i) in vivo studies using pancreatic tissue from patients with alcohol-induced chronic pancreatitis and from animal models of experimental pancreatitis and (ii) in vitro studies using cultured PSCs. These studies indicate that PSCs are activated early in the course of pancreatic injury and are the predominant source of collagen in the fibrotic pancreas. Several factors that may be responsible for mediating PSC activation during chronic alcohol exposure have also been identified. From the findings to date, it may be speculated that the pathogenesis of alcoholic pancreatic fibrosis may involve 2 pathways: (i) a necroinflammatory pathway involving cytokine release and PSC activation and (ii) a nonnecroinflammatory pathway involving direct activation of PSCs by ethanol via its metabolism to acetaldehyde and the generation of oxidant stress.
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PMID:Stellate cell activation in alcoholic pancreatitis. 1457 94

Cytokine PharmaSciences is developing semapimod (CNI-1493), a cytokine inhibitor and synthetic guanylhydrazone mitogen-activated protein kinase blocker, as a potential treatment for Crohn's disease and other inflammatory conditions. As of December 2001, a phase I study demonstrating the safety of the compound had been completed and phase II trials for psoriasis and Crohn's disease were ongoing. In April 2003, preclinical and early clinical studies were underway for a variety of indications, including congestive heart failure and pancreatitis.
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PMID:Semapimod. Cytokine. 1475 76

Acute pancreatitis is characterized by local inflammation and cytokine production, and release is thought to contribute to this process. Nuclear factor (NF)-kappaB activation and cytokine production are linked and inhibition of NF-kappaB has been shown to decrease the severity of pancreatitis. We have shown that inhibition of COX-2 ameliorates pancreatitis; however, the mechanism by which this effect occurs is unclear. Swiss Webster mice were injected intraperitoneally with either saline (control) or caerulein (CAE; 50 mg/kg) hourly for 8 hours; mice receiving CAE were further subdivided to receive saline or the cyclooxygenase-2 (COX-2) selective inhibitor (SC-58125; 10 mg, intraperitoneally) at the time of the first injection of CAE. Pancreata were harvested, histologic sections were scored, and protein was extracted to determine cytokine (interleukin [IL]-6, IL-1beta) levels and NF-kappaB subunits by ELISA and NF-kappaB activation by gel shift. In addition, serum was collected for measurement of cytokines. COX-2 inhibition resulted in decreased inflammation and a decrease in NF-kappaB activation. IL-6 and IL-1beta levels after COX-2 inhibition, however, remained elevated to levels equivalent to those of mice with histologic inflammation after CAE alone. COX-2 inhibition decreases inflammation as well as late-phase NF-kappaB activation but does not diminish levels of inflammatory cytokines, thus suggesting a two-phase activator of NF-kappaB. The attenuation of inflammation, despite unaltered cytokine levels, suggests that cytokines may not be critical for the inflammatory phase of pancreatitis.
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PMID:COX-2 inhibition results in alterations in nuclear factor (NF)-kappaB activation but not cytokine production in acute pancreatitis. 1512 Mar 78

Fibrosis in the pancreas is caused by such processes as necrosis/apoptosis, inflammation or duct obstruction. The initial event that induces fibrogenesis in the pancreas is an injury that may involve the interstitial mesenchymal cells, the duct cells and/or the acinar cells. Damage to any one of these tissue compartments of the pancreas is associated with cytokine-triggered transformation of resident fibroblasts/pancreatic stellate cells into myofibroblasts and the subsequent production and deposition of extracellular matrix. Depending on the site of injury in the pancreas and the involved tissue compartment, predominantly inter(peri)lobular fibrosis (as in alcoholic chronic pancreatitis), periductal fibrosis (as in hereditary pancreatitis), periductal and interlobular fibrosis (as in autoimmune pancreatitis) or diffuse inter- and intralobular fibrosis (as in obstructive chronic pancreatitis) develops.
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PMID:Fibrosis of the pancreas: the initial tissue damage and the resulting pattern. 1513 18

Severe impairment of exocrine pancreatic secretion has recently been demonstrated in a clinical study in sepsis and septic shock patients. The purpose of this study was to further evaluate involvement of the pancreas in the acute phase reaction in sepsis. Using a normotensive rat model of Pseudomonas pneumonia-induced sepsis, we assessed the expression of PAP-I, amylase and trypsinogen mRNA, PAPI protein levels, and cytokine expression in the pancreas by Northern and Western blot analysis and RT-M PCR, respectively. Presence of several well-established features of pancreatitis in sepsis-induced animals were examined by biochemical and histopathological methods as well as by a determination of both water and myeloperoxidase content. Sepsis resulted in an up-regulation of PAP-I gene expression and increase in its protein level in pancreas while the mRNA levels of amylase and trypsinogen were down-regulated. Differences in the pancreatic cytokine expression, serum amylase and serum lipase levels, the occurrence of pancreatic edema as well as the severity of inflammatory infiltration and necrosis were not significantly different between sham and pneumonia groups. Acinar cells showed increased vacuolization in pneumonia animals 24 hours after the treatment. These findings demonstrate that the pancreas is actively involved in the acute phase reaction in sepsis of remote origin. This involvement occurs without concomitant biochemical and histopathologic alterations observed in pancreatitis. Taken all together, these features are indicative of a sepsis-specific dysfunction of the pancreas.
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PMID:Pseudomonas pneumonia-mediated sepsis induces expression of pancreatitis-associated protein-I in rat pancreas. 1521 Nov 9

Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic inflammation and fibrosis. Trypsin and tryptase, which are agonists for protease-activated receptor-2 (PAR-2), are involved in the pathogenesis of pancreatitis. Here, we examined whether PSCs expressed PAR-2 and its agonists affect the cell functions of PSCs. PSCs were isolated from rat pancreas tissue. Expression of PAR-2 was examined by Western blotting and reverse transcription-polymerase chain reaction. Trypsin, activating peptide (SLIGRL-NH(2), corresponding to the PAR-2 tethered ligand), and tryptase were tested for their ability to affect proliferation, chemokine production, and collagen synthesis in culture-activated PSCs. Activation of mitogen-activated protein (MAP) kinases was assessed by Western blotting using antiphosphospecific antibodies. The effect of PAR-2 agonists on the activation of freshly isolated PSCs in culture was also examined. PAR-2 expression was observed in culture-activated PSCs, whereas it was undetectable in freshly isolated PSCs. PAR-2 agonists activated activator protein-1 and MAP kinases (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 MAP kinase) but not nuclear factor kappaB. PAR-2 agonists induced proliferation of PSCs through the activation of extracellular signal-regulated kinase. PAR-2 agonists increased collagen synthesis through the activation of c-Jun N-terminal kinase and p38 MAP kinase. PAR-2 agonists did not induce the production of monocyte chemoattractant protein-1 and cytokine-induced neutrophil chemoattractant-1 or initiate the transformation of freshly isolated PSCs in culture. Taken together, our results suggest a role of PAR-2 in the sustenance of pancreatic fibrosis through the increased proliferation and collagen production in PSCs.
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PMID:Protease-activated receptor-2-mediated proliferation and collagen production of rat pancreatic stellate cells. 1536 78

The systemic manifestations of acute pancreatitis (AP) are responsible for the majority of pancreatitis-associated morbidity and mortality. Recent studies have established that severe AP is a disease with systemic inflammatory response syndrome as well as compensatory anti-inflammatory response syndrome. Based on their roles in the pathogenesis of AP, new therapies have been sought and tested, including those preventing the biological activity of two pro-inflammatory cytokines, tumor necrosis factor (TNF)-alpha and interleukin-1 (IL-1). Biological activity of TNF might be blunted by anti-TNF-alpha antibody or soluble TNF receptor, and IL-1 receptor antagonist might blunt that of IL-1. Although anti-cytokine therapies against IL-1, TNF-alpha or macrophage migration inhibitory factor showed promising results in experimental models of AP, the question remains as to whether similar antagonism during clinical pancreatitis would benefit patients with severe AP. Major considerations include the suitability of AP to cytokine antagonism in clinical settings, the possibility that such a therapy may lead to the development of immunosuppression and consequent infection, and whether a therapeutic window for such antagonism
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PMID:[Anti-cytokine therapy for severe acute pancreatitis]. 1555 97

A characteristic feature of all inflammatory disorders is the excessive recruitment of leukocytes to the site of inflammation. The loss of control in trafficking these cells contributes to inflammatory diseases. Leukocyte recruitment is a well-orchestrated process that includes several protein families including the large cytokine subfamily of chemotactic cytokines, the chemokines. Chemokines and their receptors are involved in the pathogenesis of several diseases. Acute lung injury that clinically manifests as acute respiratory distress syndrome (ARDS) is caused by an uncontrolled systemic inflammatory response resulting from clinical events including major surgery, trauma, multiple transfusions, severe burns, pancreatitis, and sepsis. Systemic inflammatory response syndrome involves activation of alveolar macrophages and sequestered neutrophils in the lung. The clinical hallmarks of ARDS are severe hypoxemia, diffuse bilateral pulmonary infiltrates, and normal intracardiac filling pressures. The magnitude and duration of the inflammatory process may ultimately determine the outcome in patients with ARDS. Recent evidence shows that activated leukocytes and chemokines play a key role in the pathogenesis of ARDS. The expanding number of antagonists of chemokine receptors for inflammatory disorders may hold promise for new medicines to combat ARDS.
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PMID:Chemokines in acute respiratory distress syndrome. 1559 Oct 40


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