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Research of Mechanism of Effect of p38MAPK Inhibitor on SAP Rats Model

Author: LiuDaoLi
Tutor: WangDong
School: Luzhou Medical College
Course: Surgery
Keywords: Severe Acute Pancreatitis p38 mitogen-activated protein kinase ( of p38 MAPK ) Cytokines SB203580 p-ATF2
CLC: R576
Type: Master's thesis
Year: 2010
Downloads: 65
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Abstract

OBJECTIVE: Severe acute pancreatitis (severe acute pancreatitis, SAP) is a common clinical critically ill acute abdomen. Its abrupt onset, the disease is complex and prone to a variety of complications, the prognosis is poor, the mortality rate can be as high as 20% or more. However, its pathogenesis is unclear, and is still a lack of specific and effective medication. In recent years, studies in the occurrence and development of SAP signaling pathway in the interaction of various cytokines, resulting in a large variety of inflammatory cytokines, thereby causing a systemic inflammatory response syndrome (with systemic inflammation. This response syndrome, SIRS) could eventually lead to multiple organ failure (multiple organ failure, MOF). How to effectively regulate the production of cytokines, and prevent the occurrence of SIRS or mitigate its severity, thereby enhancing the therapeutic effect of SAP and reduce mortality to become a huge problem in front of the majority of medical workers. Has confirmed that the p38 mitogen-activated protein kinase (p38 mitogen-activated protein kinase, p38MAPK) signal transduction pathway and a variety of cytokine production is closely related to the regulation, and thus the subject rat sodium taurocholate (sodium taurocholate Tc-Na ) this path of severe acute pancreatitis model study to explore the mechanism p38MAPK inhibitor SB203580 in a rat model of severe acute pancreatitis. Methods: 45 adult male Sprague-Dawley rats were randomly divided into three groups, sham-operated group (SO), SAP group and SB203580 treatment group (SB group). 5% Tc-Na (1ml/kg) bile pancreatic duct retrograde injection SAP model. The rat preoperative 12h fasting can not help but water, anesthetized by intraperitoneal injection of 3% sodium pentobarbital (1ml/kg), routine disinfection shop towels upper abdominal midline incision 2cm Rufu. Processing blunt the 1ml syringe needles in the descending duodenum near the duodenal papilla puncture outside sidewall, since duodenal papilla retrograde piercing cholangiopancreatography end about 1cm, near the hepatic portal at smaller with no damage Pull the needle artery clip clipping near the hepatic portal cholangiopancreatography end, inject 5% Tc-Na (injection speed 0.1ml/min) Note after 5min check and confirm rat pancreatic tissue hyperemia local, release the artery clip confirm the intraperitoneal no active bleeding, two layers of the abdomen was closed, subcutaneous injection of saline (2ml/100g) lost intraoperative supplemental moisture. SB rats tail vein injection 30 minutes before surgery SB203580 (5mg/kg). N = 15 3h, 6h, 12h three time points, 5 for each time point. Laparotomy observed pancreas change changes of measured ascites, heart blood was collected approximately 3-5ml, extracted serum, serum samples were saved at -20 ℃, for subsequent detection. Organizations take the head of the pancreas, with 4% paraformaldehyde immersion fixed 24h, embedded in paraffin, sliced. Rats in each group were bled to death after lung tissue set 80 ℃ oven Continuous baking 24h to calculate the wet / dry ratio. The automated blood biochemical analyzer serum amylase and using measured by ELISA serum levels of TNF-α, IL-6, IL-10, and other cytokines. Visual observation of the pancreas, lung tissue hemorrhage, edema and other changes; HE staining, light microscopy observation of histopathological changes of the pancreas; using immunohistochemical SP method was used to observe the of ATF2 phosphorylation expression, and count the number of positive cells. Results: 1. Ascites hemorrhagic ascites: SO group; SAP group, the SB group were bloody ascites, at each time point the SB group ascites is less than the SAP group, a statistically significant (p lt; 0.01). Serum amylase: SO group serum amylase activity is low, at each time point were lower than the other two groups (p lt; 0.01); the SB group group compared with SAP group to reduce the level of, but only at 6h, 12h statistically significance (p lt; 0.01). 3. Serum cytokines: the SO group serum TNF-α, IL-6 and IL-10 concentration was significantly lower than the SAP group and SB group was statistically significant (p lt; 0.01); the SB levels of TNF-α, IL-6 concentration lower than the SAP group and IL-10, TNF-α, IL-10 at each time point were statistically significant (p lt; 0.05);. IL-6 in 6h, 12h statistical significance (p lt; 0.05) . Lung wet / dry weight ratio: the ratio of SO group at each time point lower than the SAP group and SB group, a statistically significant (P lt; 0.05); SB group each time the ratio is lower than the SAP group at 6h, 12h statistically significant (P lt; 0.05). Pancreas generally rated: SO Eye view did not change; the pathological score SAP group at each time point were significantly higher; SB group ratings are down compared to the SAP group, 6,12 hours difference was statistically significant (p lt; 0.01). 6 pancreatic histological Rating: SO group pancreatic tissue pathological changes of the SAP group, pancreatic interstitial visible infiltration of inflammatory cells and red blood oozing, and with the increased degree of progression 3h group see the pancreas, a small amount of inflammatory interstitial cell infiltration, acinar cells in a small amount of necrosis; the 6h group pancreatic interstitial exudation and inflammatory cell infiltration a large number of red blood cells, acinar cells in a wide range of severe swelling and necrosis; 12h group necrosis further expand the scope up to the entire lobular the lobular contour still see; SB treatment group also visible obvious pathological changes of pancreas, but compared with SAP group to reduce the two groups at each time point were significant differences (p lt; 0.01). Pancreatic tissue p-ATF2 expression levels: low SO group level, no significant changes at each time point; corresponding SAP group at each time point p-ATF2 expression levels were significantly higher (p lt; 0.01); SB group at each time point expression compared with SAP group decreased significantly (p lt; 0.01). Conclusions: 1. Cytokines TNF-α, IL-6, and the level of expression of the IL-10 is related to the severity of the SAP, and plays an important role in the development of the disease in the SAP. Pancreatic tissue level of p-ATF2 early in the SAP that was expressed at high levels, and to maintain a longer period of time, prompted p38MAPK signaling pathway activation with SAP condition closely related to the development of. 3. P38MAPK specific inhibitor SB203580 can downregulate the expression levels of p-ATF2, reduces the expression of inflammatory factors, improved pathological damage of the pancreas and lung. Tip p38MAPK signaling pathway plays a critical role in regulation of cytokine expression in the pathogenesis of SAP rats, the pathway can be used as the target of the SAP treatment inhibitors have the value of prevention and control of SAP applications.

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CLC: > Medicine, health > Internal Medicine > Digestive and abdominal diseases > Pancreatic diseases
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