Proinflammatory role of trypsin and protease-activated receptor-2 in a rat model of acute pancreatitis
Proinflammatory role of trypsin and protease-activated receptor-2 in a rat model of acute pancreatitis
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DOI：
10.1097/01.mpa.0000163178.37050.0d
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发表时间：
2005-07-01
期刊：
影响因子：
2.9
通讯作者：
Ogawa, M
中科院分区：
文献类型：
--
作者：
Maeda, K;Hirota, M;Ogawa, M
目的：急性胰腺炎的病理生理与胰蛋白酶的自身活化密切相关。胰蛋白酶在细胞上的生物活性归因于蛋白酶活化受体-2 （PAR-2）的活化。我们推测胰蛋白酶可能通过PAR-2信号激活急性胰腺炎的腺泡细胞或炎症细胞。方法：采用抗大鼠PAR-2裂解位点（PCS）抗体和抗大鼠PAR-2 n端片段（PNF）抗体，免疫化学方法分析PAR-2在大鼠腺泡细胞系、ARIP和大鼠胰腺中的表达。测定血浆PNF水平。此外，我们还分析了抗大鼠PCS抗体和甲磺酸那莫司他（一种强效胰蛋白酶抑制剂）对急性胰腺炎期间PAR-2激活的影响。结果：ARIP细胞表达par2， par2被外源性胰蛋白酶活性激活。我们还发现PAR-2在胰腺腺泡和胰管细胞中强烈表达，并在大鼠核蛋白诱导的急性胰腺炎中被激活。抗大鼠PCS抗体和甲磺酸那莫他可减少白细胞介素-6和干扰素γ的产生，减轻远端器官损伤。结论：这些结果提示胰蛋白酶及其特异性受体PAR-2在大鼠急性胰腺炎时细胞因子的产生和远处脏器损伤中起重要作用。
Objectives: The pathophysiology of acute pancreatitis is strongly associated with autoactivation of trypsin. The biologic activity of trypsin on cells is attributed to the activation of protease-activated receptor-2 (PAR-2). We hypothesize that trypsin may activate acinar cells or inflammatory cells through PAR-2 signals in acute pancreatitis.Methods: We immunochemically analyzed the expression of PAR-2 in the rat acinar cell line, ARIP, and the rat pancreas, using anti-rat PAR-2 cleavage site (PCS) and anti-rat PAR-2 N-terminal fragment (PNF) antibodies. Plasma levels of PNF were determined. Furthermore, the effects of the anti-rat PCS antibody and nafamostat mesylate, a potent trypsin inhibitor, on PAR-2 activation during acute pancreatitis were also analyzed.Results: ARIP cells expressed PAR-2, which was activated by exogenous trypsin activity. We also showed that PAR-2 is strongly expressed in pancreatic acinar and duct cells and that it is activated in rat cerulein-induced acute pancreatitis. The anti-rat PCS antibody and nafamostat mesylate reduced interleukin-6 and interferon gamma production and alleviated distant organ injury.Conclusions: These results suggest that trypsin and its specific receptor, PAR-2, play an important role in cytokine production and the resultant development of distant organ injury during rat acute pancreatitis.