Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001339 (acute pancreatitis)
 10,593 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic inflammatory response syndrome (SIRS) is typically associated with trauma, surgery, or acute pancreatitis. SIRS resembles sepsis, triggered by exogenous macromolecules such as LPS acting on Toll-like receptors. What triggers SIRS in the absence of infection, however, is unknown. In this study, we report that a SIRS-like response can be induced in mice by administration of soluble heparan sulfate, a glycosaminoglycan associated with nucleated cells and extracellular matrices, and by elastase, which cleaves and releases heparan sulfate proteoglycans. The ability of heparan sulfate and elastase to induce SIRS depends on functional Toll-like receptor 4, because mutant mice lacking that receptor or its function do not respond. These results provide a molecular explanation for the initiation of SIRS.
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PMID:Cutting edge: an endogenous pathway to systemic inflammatory response syndrome (SIRS)-like reactions through Toll-like receptor 4. 1468 4

Pancreatic elastase has been implicated in the pathophysiology of severe acute pancreatitis, characterized by systemic inflammatory response, distant organ failure, and high mortality. Here we show that pancreatic elastase activates transcription factors NF-kappaB, AP-1, and NFAT in human myeloid cells (U-937 and THP-1) in culture. Pancreatic elastase also induces TNF-alpha secretion and increased expression of CD11b in THP-1 cells which can be inhibited by neutralizing anti-Toll-like receptor 4 (TLR4) antibodies. NF-kappaB blocking agents (MG-132, PGA1) prevented elastase-induced TNF-alpha secretion from THP-1 cells. Our results suggest that pancreatic elastase-induced proinflammatory effects are mediated by TLR4 and NF-kappaB in human myeloid cells.
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PMID:Proinflammatory effects of pancreatic elastase are mediated through TLR4 and NF-kappaB. 1535 20

This paper was aimed to detect Toll-like receptor 4 (TLR4) microcirculatory expression and localization in rat pancreas and intestine. Acute pancreatitis (AP) was induced by twice injections of cerulein (20 mug in total) and acute necrotizing pancreatitis (ANP) was induced by intraductal injection of 5% taurocholate (1 ml/kg.bw). Reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) were used to detect and localize TLR4 in the pancreas and intestine. Results showed that RT-PCR of RNA isolated from pancreatic and intestinal tissue yielded the predicted amplicon for TLR4; IHC analysis localized TLR4 expression to the endothelium of pancreatic arteriole, venule, acinar capillary network and sinusoidal capillary of endocrine islet; TLR4 expression in intestine was principally in the microvascular endothelium and leucocytes within the mucosa lamina propria. TLR4 staining in intestine was more intense in taurocholate-induced pancreatitis (TIP) than that in cerulein-induced pancreatitis (CIP). In conclusion, TLR4 could be detected in the pancreatic and intestinal microcirculation, suggesting TLR4 involved in the microcirculatory impairment in AP; the more intense intestinal TLR4 expression in TIP suggests a potential risk for secondary infection.
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PMID:Microcirculatory detection of Toll-like receptor 4 in rat pancreas and intestine. 1654 39

Acute pancreatitis accompanied by a subsequent infectious attack can often lead to multisystem organ dysfunction, including acute lung injury (ALI), but the molecular mechanisms are poorly defined. In this study, we explored the role of the priming insult by induction of cerulein pancreatitis, which was followed by the second attack due to endotoxemia, in the development of ALI in mice. Experiments revealed that LPS injection in mice with acute pancreatitis caused the development of ALI, as indicated by blood-gas derangements, pulmonary vascular hyperpermeability, increased inflammatory cell counts in bronchoalveolar lavage, and histologic lung damage. This was associated with the pancreatitis-induced increase in expression of macrophage migration inhibitory factor (MIF) in the lungs, together with elevated expression of Toll-like receptor (TLR)-4, both of which were inhibited by administration of anti-protease-activated receptor (PAR)-2 antibody. Furthermore, anti-MIF antibody treatment suppressed the pancreatitis-induced elevation of TLR-4 pulmonary expression. Genetic removal of MIF from mice resulted in less development of ALI in the setting of acute pancreatitis complicated by endotoxemia. These findings demonstrate that activation of protease-activated receptor-2 with trypsin, which can be released after pancreatitis induction, positively regulates the transcript level of MIF, and increased MIF results in exaggerated pulmonary expression of TLR-4, leading to the development of ALI with a subsequent infectious attack. We thus suggest that interventions designed to modulate MIF may have therapeutic advantages in treating ALI in patients with acute pancreatitis complicated by bacterial infection.
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PMID:Role of macrophage migration inhibitory factor in acute lung injury in mice with acute pancreatitis complicated by endotoxemia. 1657 46

We sought to study Toll-like receptor 4 (TLR4) expression on peripheral blood mononuclear cells (PBMCs) during the early stage of human acute pancreatitis (AP). Thirty consecutive patients with acute pancreatitis admitted within 24 hr of onset of abdominal pain were enrolled prospectively in this study. Blood samples were taken by venipuncture at admission and on the third and seventh days after admission. PBMCs were isolated, and TLR4 and CD14 expression on PBMCs was detected by flow cytometer. Serum tumor necrosis factor (TNF)-alpha, interleukin, and lipase were detected simultaneously. Relations among these parameters were analysis. In mild AP, TLR4 expression increased on the first day of admission and then continued to decline for several days. On the seventh day, TLR4 expression was almost normal compared with that of the normal control. The alteration of serum TNF-alpha was coincidence with TLR4. We conclude that mononuclear-macrophages might be ignited through TLR4 (the gatekeeper of the innate immune system) and lead to production of TNF-alpha.
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PMID:Alterations of Toll-like receptor 4 expression on peripheral blood monocytes during the early stage of human acute pancreatitis. 1741 54

In severe acute pancreatitis (SAP), immunologic impairment in the early phase may be linked to subsequent infectious complications that are main contributor to the high mortality. Toll-like receptors (TLRs) recognize microorganisms as the innate immune system, and are involved in host defense mechanism. TLR2 recognizes lipoteichoic acid (LTA) of gram-positive bacteria, and TLR4 recognizes lipopolysaccharide (LPS) of gram-negative bacilli. This study aimed to investigate the expression of TLRs on macrophages and their TLRs-mediated cytokine production in rat SAP. SAP was induced by retrograde injection of 3% sodium deoxycholate into the biliopancreatic duct in male Wistar rats. Macrophages were isolated from bronchoalveolar lavage fluid 6 hours after induction of SAP. The expression of TLR2 and TLR4 was analyzed by real-time RT-PCR and western blotting. TNF-alpha release from macrophages was estimated after 4-hour stimulation of LTA or LPS. Endotoxin/bacterial translocation (E/BT) was also evaluated in this model. The expression of TLR2 (mRNA and protein) and LTA-mediated TNF-alpha production were significantly decreased in SAP compared with control. The expression of TLR4 (mRNA and protein) and LPS-mediated TNF-alpha production was also significantly decreased in SAP compared with control. E/BT occurred 18 hours after induction of SAP. These results suggest that the impaired responsiveness to LTA and LPS of macrophages is derived from decreased expression of TLR2 and TLR4, respectively. This suppression of immune response in the early phase may be implicated in the mechanism of infectious complications.
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PMID:Decreased expression of Toll-like receptor 2 and 4 on macrophages in experimental severe acute pancreatitis. 1820 98

Acute pancreatitis (AP) activates the systemic inflammatory response and is potentially lethal. Recent studies demonstrated that pancreatic enzymes could induce cytokine expression via Toll-like receptor 4 (TLR4) signal pathway, indicating a possible role of TLR4 in local pancreatic injury and systemic inflammatory response. Emodin, an anthraquinone derivative from Radix et Rhizoma Rhei, and baicalin, a flavone from Scutellaria baicalensis Georgi, both have been reported to possess anti-inflammatory activities. In present study, we investigated the combined effect of emodin and baicalin on pancreatic damage and pancreatitis associated lung injury, as well as tissue TLR4 expression in the setting of AP. The results showed that combination of emodin and baicalin significantly reduced serum amylase, tumor necrosis factor-alpha and interleukin-6, attenuated pancreatic and pulmonary damage, also suppressed TLR4 expression in pancreas and lung. It could be speculated that amelioration of pancreatic and pulmonary damage by emodin and baicalin might contribute, in part at least, to the suppression of TLR4 expression. The present study provides beneficial evidence as to simultaneous treatment for AP, and also suggests an important role of TLR4 in pathophysiology of AP.
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PMID:Up-regulation of Toll-like receptor 4 was suppressed by emodin and baicalin in the setting of acute pancreatitis. 1834 29

This study evaluated the association of the polymorphisms in the Toll-like receptor (TLR)2 and TLR4 genes with acute pancreatitis (AP) in Japan. The numbers of guanine-thymine [(GT)n] repeats in intron 2 of the TLR2 gene were counted in 202 unrelated patients with AP (80 with severe and 122 with mild disease) and in 286 healthy controls, using polymerase chain reaction and Genescan analysis. The alleles were divided into three subclasses: (GT)16 or less as the S allele; between (GT)17 and (GT)22 as the M allele; and (GT)23 or more as the L allele. Asp299Gly and Thr399Ile polymorphisms in the TLR4 gene were examined by polymerase chain reaction-restriction fragment length polymorphism analysis. Patients with AP had more S alleles (p < 0.001; odds ratio = 2.37; 95% confidence interval = 1.78-3.17) and fewer M alleles (p < 0.001; odds ratio = 0.40; 95% confidence interval 0.31-0.52) than did healthy controls. Genotypes SS and SL were more common, whereas MM and ML were less common in patients with AP. In subgroup analyses, the genotypes including S alleles were more common in patients with severe AP than in controls. No Asp299Gly and Thr399Ile polymorphisms were detected. In conclusion, microsatellite polymorphism in intron 2 of the TLR2 gene was associated with susceptibility to AP and its severity in Japan.
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PMID:Microsatellite polymorphism in intron 2 of human Toll-like receptor 2 gene is associated with susceptibility to acute pancreatitis in Japan. 1928 Jul 17

To investigate the effect of salvia miltiorrhizae on the expressions of TLR4 protein in the liver of rats with severe acute pancreatitis (SAP) and obstructive jaundice (OJ), and explore the protective mechanism of salvia miltiorrhizae on the liver of rats. A total of 288 mice was used in SAP- (n = 108) and OJ-associated experiments (n = 180). The rats were randomly divided into sham-operated, model control and treated group. Based on the different time points after operation, these groups were subdivided into 3, 6 and 12 h subgroups (SAP rats, n = 12) or 7, 14, 21 and 28 days subgroups (OJ rats, n = 15). At the corresponding time points after operation, blood and liver specimens were collected to determine the contents of endotoxin and TNF-alpha in the blood as well as the expression levels of TLR4 protein in the liver. Compared with the corresponding model control group, though the number of dead SAP or OJ rats in the treated group declined, no statistical difference was noted; The levels of plasma endotoxin in SAP (at 6 and 12 h) or OJ rats in the treated group decreased significantly (P < 0.001 and P < 0.01, respectively); The levels of serum TNF-alpha in SAP (at 12 h) or OJ rats (on 14 days) declined (P < 0.001 and P < 0.01, respectively); The staining intensity as well as the product of staining intensity and positive rate of TRL4 protein only significantly declined on 7 and 28 days in OJ rats (P < 0.01). On 7 days, treated group in positive rate of TLR4 protein were significantly lower than that in model control group (P < 0.01). The pathological changes in different treated groups of SAP and OJ rats were improved. Salvia miltiorrhizae is able to reduce the levels of plasma endotoxin and inhibit effectively the expressions of TLR4 protein in the liver of SAP or OJ rats, thereby decreasing inflammatory reaction and exerting protective effect on liver function.
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PMID:Effect of salvia miltiorrhizae on the expressions of TLR4 protein in the liver of rats with SAP or OJ. 1937 Apr 6

Because the mechanism underlying the development of acute pancreatitis (AP) has not yet been fully clarified, it has been a hot but difficult topic in basic and clinical research for a long time. Currently, the dominant hypothesis for the pathogenesis of AP is that it is a disease of self-digestive acute chemical inflammation induced by trypsin activation. As proteins to trigger the inflammatory response cascade, Toll-like receptors (TLRs), especially TLR4, provide a new clue for studying the pathogenesis of AP from the source. Some studies have found that when TLR4 is activated by certain factors, it can amplify an inflammatory effect and aggravate the body's inflammatory response through a series of signal transduction. Toll-like receptor 4 may play an important role in the synthesis and release of proinflammatory cytokines, and the up-regulation of the TLR4 gene may be related with the development and progression of multiple organ injury during AP. As the "gate" of inflammatory response, TLR4 may be closely associated with the development and progression of multiple organ injury during AP. Understanding the roles of TLR4 in AP will help to further clarify the pathogenesis of AP and to search a new target for the treatment of AP.
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PMID:Possible role of toll-like receptor 4 in acute pancreatitis. 2066 79


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