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)

Treatments for pancreatitis are limited. Activation of transcription factor NF-kappaB, a key regulator of inflammatory molecule expression, is an early event in experimental pancreatitis and correlates with the inflammatory response. We report here that curcumin, a natural phytochemical known to inhibit NF-kappaB and activator protein (AP)-1, another important proinflammatory transcription factor, ameliorates pancreatitis in two rat models. In both cerulein pancreatitis and pancreatitis induced by a combination of ethanol diet and low-dose CCK, curcumin improved the severity of the disease as measured by a number of parameters (histology, serum amylase, pancreatic trypsin, and neutrophil infiltration). Curcumin markedly inhibited NF-kappaB and AP-1 activation, assessed by DNA binding and degradation of inhibitory IkappaB proteins, and the induction of mRNAs for cytokines IL-6 and TNF-alpha, the chemokine KC, and inducible nitric oxide synthase in pancreas. Curcumin also blocked CCK-induced NF-kappaB and AP-1 activation in isolated pancreatic acini. Our findings indicate that blocking key signals of the inflammatory response ameliorates pancreatitis in both ethanol and nonethanol models. They suggest that curcumin, which is currently in clinical trials for cancer prevention, may be useful for treatment of pancreatitis.
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PMID:Curcumin ameliorates ethanol and nonethanol experimental pancreatitis. 1248 37

Acute pancreatitis is an inflammatory process of variable severity, and leukocytes are thought to play a key role in the development of pancreatitis and pancreatitis-associated lung injury. The effects of mediators released by these inflammatory cells may induce tissue damage. The aim of our study was to evaluate the role of the chemokine, macrophage inflammatory protein-2 (MIP-2), in the pathogenesis of cerulein-induced pancreatitis and pancreatitis-associated lung injury. The severity of pancreatitis was measured by serum amylase, pancreatic edema, acinar cell necrosis, and myeloperoxidase activity. Lung injury was quantitated by evaluating lung microvascular permeability and lung myeloperoxidase activity. To determine the role of MIP-2 in the pathophysiology of the disease, anti-MIP-2 antibody was administered either 1 hour before or 2 hours after the start of cerulein administration. MIP-2 concentrations increased in serum, pancreas, and lung tissues in mice treated with cerulein. Anti-MIP-2 antibody administrated either before or after cerulein partially protected against pancreas and lung injury. These results show that MIP-2 plays a key role in the pathophysiology of acute pancreatitis and that MIP-2 blockade may improve the outcome of the disease.
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PMID:Role of macrophage inflammatory peptide-2 in cerulein-induced acute pancreatitis and pancreatitis-associated lung injury. 1269 50

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

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

Patients with compensatory anti-inflammatory response syndrome (CARS) are at a higher risk for infection with various opportunistic pathogens. CARS develops commonly in association with the manifestation of systemic inflammatory response syndrome (SIRS). In the present study, the role of SIRS-associated soluble factors on the CARS development was examined in mice with pancreatitis, a carrier of typical SIRS. Following the production of SIRS-related cytokines [tumor necrosis factor alpha and interleukin (IL)-1beta], CC chemokine ligand 2 (CCL2), IL-4, and IL-10 (typical CARS cytokines) were detected in the sera of mice with pancreatitis. CCL2 has been described as an essential chemokine for the T helper cell type 2 manifestation. CARS effector cells (cells with an ability to produce IL-4 and IL-10) were not generated from normal T cells after stimulation with SIRS-related cytokines. However, these cells were generated from normal T cells after cultivation with peripheral blood neutrophils (PMN) from SIRS mice in a dual-chamber transwell. Normal T cells did not convert to CARS effector cells after transwell cultures with PMN from normal mice. CCL2 was detected in culture fluids of PMN from SIRS mice, and PMN from normal mice did not produce CCL2 into their culture fluids. CARS effector cells did not appear in PMN-depleted SIRS mice or SIRS mice treated with anti-CCL2 monoclonal antibody, and these cells were demonstrated in PMN-depleted SIRS mice after treatment with recombinant murine CCL2. These results indicate that CCL2 produced by PMN from SIRS mice is an active molecule on the SIRS-associated CARS manifestation.
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PMID:CCL2 as a trigger of manifestations of compensatory anti-inflammatory response syndrome in mice with severe systemic inflammatory response syndrome. 1643 96

Exocrinopathy and pancreatitis-like injury were developed in C57BL/6 (B6) mice infected with LP-BM5 murine leukemia virus, which is known to induce murine acquired immunodeficiency syndrome (MAIDS). The role of chemokines, especially CXCL10/interferon (IFN)-gamma-inducible protein 10 (IP-10), a chemokine to attract CXCR3+ T helper 1-type CD4+ T cells, has not been investigated thoroughly in the pathogenesis of pancreatitis. B6 mice were inoculated intraperitoneally with LP-BM5 and then injected every week with either an antibody against IP-10 or a control antibody. Eight weeks after infection, we analyzed the effect of IP-10 neutralization. Anti-IP-10 antibody treatment did not change the generalized lymphadenopathy and hepatosplenomegaly of mice with MAIDS. The treatment significantly reduced the number of IP-10- and CXCR3-positive cells in the mesenteric lymph nodes (mLNs) but not the phenotypes and gross numbers of cells. In contrast, IP-10 neutralization reduced the number of mononuclear cells infiltrating into the pancreas. Anti-IP-10 antibody treatment did not change the numbers of IFN-gamma+ and IL10+ cells in the mLN but significantly reduced their numbers, especially IFN-gamma+ and IL-10+ CD4+ T cells and IFN-gamma+ Mac-1+ cells, in the pancreas. IP-10 neutralization ameliorated the pancreatic lesions of mice with MAIDS probably by blocking the cellular infiltration of CD4+ T cells and IFN-gamma+ Mac-1+ cells into the pancreas at least at 8 wk after infection, suggesting that IP-10 and these cells might play a key role in the development of chronic autoimmune pancreatitis.
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PMID:Role of IP-10/CXCL10 in the progression of pancreatitis-like injury in mice after murine retroviral infection. 1682 61

Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction and to the subsequent systemic inflammatory response, which may result in multiple organ dysfunction and death. Inflammatory mediators, including chemokines and substance P (SP), are known to play a crucial role in the pathogenesis of acute pancreatitis. It has been shown that pancreatic acinar cells produce the chemokine monocyte chemoattractant protein-1 (MCP-1) in response to caerulein hyperstimulation, demonstrating that acinar-derived MCP-1 is an early mediator of inflammation in acute pancreatitis. Similarly, SP levels in the pancreas and pancreatic acinar cell expression of neurokinin-1 receptor, the primary receptor for SP, are both increased during secretagogue-induced experimental pancreatitis. This study aims to examine the functional consequences of exposing mouse pancreatic acinar cells to SP and to determine whether it leads to proinflammatory signaling, such as production of chemokines. Exposure of mouse pancreatic acini to SP significantly increased synthesis of MCP-1, macrophage inflammatory protein-1alpha (MIP-1alpha), as well as MIP-2. Furthermore, SP also increased NF-kappaB activation. The stimulatory effect of SP was specific to chemokine synthesis through the NF-kappaB pathway, since the increase in chemokine production was completely attenuated when pancreatic acini were pretreated with the selective NF-kappaB inhibitor NF-kappaB essential modulator-binding domain peptide. This study shows that SP-induced chemokine synthesis in mouse pancreatic acinar cells is NF-kappaB dependent.
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PMID:Substance P treatment stimulates chemokine synthesis in pancreatic acinar cells via the activation of NF-kappaB. 1687 95

Acute pancreatitis is a common, and as yet incurable, clinical condition, the incidence of which has been increasing over recent years. Chemokines are believed to play a key role in the pathogenesis of acute pancreatitis. We have earlier shown that treatment with a neutralizing antibody against CINC, a CXC chemokine, protects rats against acute pancreatitis-associated lung injury. The hexapeptide antileukinate (Ac-RRWWCR-NH2) is a potent inhibitor of binding of CXC chemokines to the receptors (CXCR2). This study aims to evaluate the effect of treatment with antileukinate on acute pancreatitis and the associated lung injury in mice. Acute pancreatitis was induced in adult male Swiss mice by hourly intra-peritoneal injections of caerulein (50 microg/kg/h) for 10 h. Antileukinate (52.63 mg/kg, s.c.) was administered to mice either 30 min before or 1 h after starting caerulein injections. Severity of acute pancreatitis was determined by measuring plasma amylase, pancreatic water content, pancreatic myeloperoxidase (MPO) activity, pancreatic macrophage inflammatory protein-2 (MIP-2) levels and histological examination of sections of pancreas. A rise in lung MPO activity and histological evidence of lung injury in lung sections was used as criteria for pancreatitis-associated lung injury. Treatment with antileukinate protected mice against acute pancreatitis and associated lung injury, showing thereby that anti-chemokine therapy may be of value in this condition.
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PMID:Treatment with antileukinate, a CXCR2 chemokine receptor antagonist, protects mice against acute pancreatitis and associated lung injury. 1701 19

This year has witnessed substantial advances in receptor biology and signal transduction that are relevant to the function and regulation of the healthy pancreas and to the pathogenesis and potential therapy of pancreatitis and pancreatic carcinoma. There has been an expansion in the cast of pancreatic regulatory molecules, now including protease-activated receptors, chemokines, and chemokine receptors. There have been new insights into the cellular distribution and signaling initiated at the classic pancreatic receptors. There have also been dramatic advances in insights into the structure of G protein-coupled receptors, with the first solution of a crystal structure of a member of this superfamily, and into the molecular basis of ligand binding and activation of these important molecules. This will clearly improve the opportunities for the rational design and refinement of receptor-active drugs. In addition to these fundamental advances, there has been renewed attention to the expression, function, and regulation of receptors and signaling pathways in pancreatic cells present in the setting of pancreatitis and pancreatic carcinoma. It is hoped that this will contribute toward earlier diagnosis, more successful therapy, and new chemopreventive strategies for these illnesses.
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PMID:Receptor biology and signal transduction. 1703 Nov 93

In association with the systemic inflammatory response syndrome (SIRS), anti-inflammatory response syndrome is commonly manifested in patients with trauma, burn injury, and after major surgery. These patients are increasingly susceptible to infection with various pathogens due to the excessive release of anti-inflammatory cytokines from anti-inflammatory effector cells. Recently, CC-chemokine ligand 2 (CCL2) found in the sera of mice with pancreatitis was identified as an active molecule for SIRS-associated anti-inflammatory response manifestation. Also, the inhibitory activity of glycyrrhizin (GL) on CCL2 production was reported. Therefore, the effect of GL on SIRS-associated anti-inflammatory response manifestation was investigated in a murine SIRS model. Without any stimulation, splenic T cells from mice 5 days after SIRS induction produced cytokines associated with anti-inflammatory response manifestation. However, these cytokines were not produced by splenic T cells from SIRS mice previously treated with GL. In dual-chamber transwells, IL-4-producing cells were generated from normal T cells cultured with peripheral blood polymorphonuclear neutrophils (PMN) from SIRS mice. However, IL-4-producing cells were not generated from normal T cells in transwell cultures performed with PMN from GL-treated SIRS mice. CCL2 was produced by PMN from SIRS mice, while this chemokine was not demonstrated in cultures of PMN from SIRS mice treated with GL. These results indicate that GL has the capacity to suppress SIRS-associated anti-inflammatory response manifestation through the inhibition of CCL2 production by PMN.
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PMID:Glycyrrhizin inhibits the manifestations of anti-inflammatory responses that appear in association with systemic inflammatory response syndrome (SIRS)-like reactions. 1711 6


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