| Background and purpose:Acute pancreatitis is an acute inflammatory process of the pancreas, often involving peripancreatic tissues and organs, sometimes even a remote system of organizations. The severity of the disease vary widely, from only slight edema of the pancreas to cause multiple organ failure and death. Acute pancreatitis is mainly related to the pathophysiology of pancreatic inflammation, edema, necrosis and pancreatic inflammation and injury of other organs. Overall mortality in patients with acute pancreatitis close to 5%.Mild acute pancreatitis and severe acute pancreatitis, the incidence ratio between about 80% vs 20%, In most patients, pancreatitis in acinar cell injury and local inflammation will subside, but in some cases, development of the disease to systemic diseases. Systemic inflammatory response syndrome (SIRS) is a difficult to control appears likely to cause local inflammation and multiple organ failure. Organ failure occurred more commonly in severe acute necrotizing pancreatitis. People generally believe that the severity of pancreatitis may be affected by the incident to determine the extent of acinar cell injury. Start early inflammatory response, inflammatory cytokines and chemokines produced by the acinar cells may have the original signal, resulting in neutrophils and macrophages and other inflammatory cell infiltration, and neutrophil aggregation,which local changes have been shown to be an important regulator of serious reactions and systemic factors. Inflammatory cell recruitment and activation of various inflammatory cells and acinar cells leads to further damage, such as tumor necrosis factor (TNF), interleukin (IL)-1 and IL-2 and IL-6 and other chemokines. These inflammatory mediators in the pancreatic acinar cell damage body cells and play an important regulatory role.Mediated intracellular signal transduction mechanism of inflammatory response in pancreatitis have been identified, including MAPK kinase module, nuclear factor-kB (NF-kB), activator protein-1 (AP-1), and phospholipids Inositol 3 kinase (PI-3K). p38MAP kinases are activated in experimental pancreatitis and play an important role in the pathogenesis,inhibition of these signals has been shown to reduce inflammation and improve on the severity of pancreatitis has a distinct role.Cytokines produced by pancreatic acinar cells may mediate pancreatic acinar ce-lls death.Mouse pancreatic acinar cells secrete inflammatory cytokines,such as TNF-a, IL-6, KC, MCP-1, MIP-2, NF-kB, AP-1.Studies have shown that p38MAPK activa-tion existed in the early activation of pancreas cells, at the same time inflammatory cell infiltration into the tissue. p38 MAPK can be activated by different stress. Recent data show that, p38MAPK mediates the cell, including TNF-a, IL-1β,IL-6, IL-8 production and expression. This control mechanism is used only at the beginning of the argument. The pancreatic acinar cells are the origin of the expression of cytokines. By RT-PCR, Western blot, immunocytochemistry and other methods shows that a large number of monocyte chemoattractant protein-1 and IL-6 and TNF and the other a large number of cytokines. The expression of cytokines may be P38MAPK inhibitors or partially inhibited NF-kB inhibitors. P38MAPK inhibitor, such as SB203580 inhibited the cytokine mRNA expressionTumour necrosis factor (TNF) is a pleiotropic cytokine, the activities of which include effects on gene expression, cell growth and cell death. The biological signalling mechanisms which are responsible for these TNF effects remain largely unknown. p38 mi to gen-activated protein kinase (MAPK) is involved in TNF-induced cytokine expression. Being a kind of automatic and gene-controlled cell death, cell apoptosis involves complicated regulatory mechanism and stimulates no inflammation, which is essentially different from necrosis. Many researches proved that the apoptosis of pancreatic acinal cells, which might be a protective reaction, had been observed both in experimental and clinical acute pancreatitis, and it had shown an inverse correlation with the severity of diseases. Severe acute pancreatitis, especially in the early stage of SAP produced a large number of TNFα, in animal experiments and clinical have confirmed significantly increased TNFa can induce endotoxemia, cause multiple organ dysfunction syndrome, but at this time, TNFa is not a protective effect for pancreatic, a reasonable explanation is:SAP occurs, the body had violently inflammatory response, induction of apoptosis is a complex process, resulting in excessive TNFa on the body more harm than protection.Severe acute pancreatitis (SAP) is a commonly encountered intra-abdominal catastrophe and is a world-wide problem. At the present time, no specific therapy has been shown to be uniformly effective in reducing the mortality,or indeed, the morbidity resulting from it. The current principles of treatment of SAP remain the same as in the previous century, using supportive therapy. The constituents of supportive therapy have undergone a number of refinements; however, as yet, there is no treatment that can downregulate the powerful systemic inflammatory.By restraining the initial signals of the pancreatic acinar cell, we can prevent the releasing of the cytokines and the chemokines originated from it, and abate the damage to pancreatic acinar cell. Studies on this domain remain insufficient. The experiment try to tell whether we can prevent the occurrence of the inflammation more radically by restraining the upstream regulatory factors, and to explore the role of P38 mitogen-activated protein kinase (MAPK) inhibitor to the expression of TNF-a and apoptosis of pancreatic acinar cells on severe acute pancreatitis in rat.Methods:Sixty-three Wistar rats were randomly allocated into three groups:sham operati -on group (group S), SAP group (group P), treatment group with SB203580 (group T). There were 21 rats in each group. Rat SAP model was induced by retrograde injection of 5% sodium taurocholate to pancreatic duct. After the model was successfully estab-lished, no treatments were given in group P. In group T, SB203580 (10mg/ml) was given by intraperitoneal injection (10 mg/kg). The rats in group S were only subjected to abdominal opening surgery.The rats were killed 1h,2h and 4h after operation. Serum levels of tumor necrosis factor-a (TNF-a) were measured by ELISA. The pancreas tissues were obtained to examine the changes with microscope, the expression of p-p38MAPK was examined by immunohistochemical technique and apoptosis of pancreatic acinar cells was detected by TUNEL methods. The data was performed by one-way analysis of variance using SPSS versionl3.0. Summary statistics were expressed as the means±the standard deviations. In all statistical analyses, a value of P<0.05 was considered statistically significant. Results:At the three time points, the levels of TNF-a and the activity of p38MAPK in groups P and T were significantly increased compared to those in group S(P<0.05). In group T, the levels of TNF-a and the activity of p38MAPK were significantly decreased compared to those in group P (P<0.05), the apoptoic rate of pancreatic acinar cell was significantly higher than those in group P (P<0.05). Pancreatic pathological damages were much milder in group T than those in group P under microscope.Conclusion:1. p38MAPK activation occurs in the early progression of severe acute pancreatitis, indicating it involvement in the starting process of severe acute pancreatitis.2. p38MAPK activation accompanied by increased expression of TNF-a in serum in severe acute cellular, using p38MAPK inhibitor SB203580 can inhibit p38MAPK activation,and accompanied by reducing the expression of TNF-a, This phenomenon indicate that the p38MAPK inhibitor SB203580 may regulate the cytokine TNF-a production.3. severe acute pancreatitis acinar cells exist some apoptosis, using the p38MAPK inhibitor SB203580 can upregulate apoptosis rate, reduce the pathological damage of the pancreas. |
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