Activated protein C, an anticoagulant polypeptide, ameliorates severe acute pancreatitis via regulation of mitogen-activated protein kinases
Activated protein C, an anticoagulant polypeptide, ameliorates severe acute pancreatitis via regulation of mitogen-activated protein kinases
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DOI：
10.1007/s00535-007-2104-2
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发表时间：
2007-11-01
影响因子：
6.3
通讯作者：
Yuan, Yaozong
中科院分区：
文献类型：
--
作者：
Chen, Ping;Zhang, Yongping;Yuan, Yaozong
背景资料。本研究旨在探讨活化蛋白C(APC)对重症急性胰腺炎(SAP)大鼠血清丝裂原活化蛋白激酶(MAPKs)表达的影响，并探讨其与SAP病情变化的关系，为临床治疗提供依据。方法：研究方法。SD大鼠在SAP诱导前静脉注射生理盐水(SAP组)、APC(50 mU g/kg或10 mU g/kg)或CNI1493。其中一组为假手术组(对照组)。实验标本在SAP诱导16h后取材。用基因芯片检测胰腺MAPKs的基因表达。检测胰腺组织中p38MAPK、细胞外信号调节蛋白激酶(ERK)1/2和c-jun氨基末端激酶(JNK)的mRNA和蛋白/磷酸化水平，以及肿瘤坏死因子(TNF)-α和白介素1β(IL-1β)的蛋白水平。通过胰腺组织学、胰腺湿/干重比值和血清淀粉酶水平评估病情严重程度。结果。APC(50 mU g/kg)或CNI1493治疗组大鼠胰腺组织中p38MAPK和JNK的表达和活性降低(与SAP组比较，P<；0.01)，减轻了胰腺炎的严重程度和胰腺组织中TNF-α和IL-1β蛋白的表达。APC处理组ERK1/2的表达和活性均增加，尤其是APC 50 mg/kg组(与SAP组和CNI1493组相比，P均<0.01)。结论。APC抑制胰腺p38MAPK和JNK的表达，上调ERK1/2的表达，可能对胰腺损伤具有保护作用，从而减轻疾病的严重程度。
Background. Our aim was to investigate the changes of mitogen-activated protein kinases (MAPKs) by activated protein C (APC) treatment in rats with severe acute pancreatitis (SAP), and relate them to changes in SAP severity, thus providing evidence for developing clinical therapies. Methods. Sprague-Dawley rats were given an intravenous injection of saline (SAP group), APC (50 mu g/kg or 10 mu g/kg), or CNI1493 just before SAP induction. One group of rats underwent a sham operation (control group). Experimental samples were harvested 16h after SAP induction. The gene expression of pancreatic MAPKs was evaluated by cDNA microarrays. The mRNA and protein/phosphorylated protein levels of p38 MAPK, extracellular signal-regulated protein kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK) and the protein levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta were determined in pancreatic tissue. The severity of disease was evaluated by pancreatic histology, the pancreatic wet/dry weight ratio, and the serum amylase level. Results. In rats treated with APC (50 mu g/kg) or CNI1493, the severity of pancreatitis and expression of pancreatic TNF-alpha and IL-1 beta proteins were attenuated by the decreased expression and activity of p38 MAPK and JNK (vs. the SAP group, P < 0.01). The expression and activity of ERK1/2 were increased in APC-treated rats, especially in the group treated with APC 50 mu g/kg (vs. the SAP or CNI1493-treated group, P < 0.01, respectively). Conclusions. Inhibition of expression of pancreatic p38 MAPK and JNK and upregulation of ERK1/2 expression by APC treatment may protect against pancreatic injury, thus ameliorating severity of the disease.