Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis
Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis
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DOI：
10.1152/ajpgi.00296.2012
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发表时间：
2013-03-01
影响因子：
4.5
通讯作者：
Perides, G.
中科院分区：
文献类型：
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作者：
Michael, E. S.;Kuliopulos, A.;Perides, G.
Michael ES、Kuliopulos A、Covic L、Steer ML、Perides G。pepducin P2pal-18S 对 PAR2 的药理学抑制可保护小鼠免受急性实验性胆源性胰腺炎。 Am J Physiol Gastrointest Liver Physiol 304：G516-G526，2013。首次发表于 2012 年 12 月 28 日； doi:10.1152/ajpgi.00296.2012.-胰腺腺泡细胞表达蛋白酶激活受体-2 (PAR2)，该受体由胰蛋白酶样丝氨酸蛋白酶激活，并已被证明对实验性胰腺炎的严重程度发挥模型特异性作用，即 PAR2(-/-) 小鼠免受实验性急性胆源性胰腺炎的影响，但会发展为更严重的促分泌素诱导的胰腺炎胰腺炎。 P2pal-18S 是一种新型 pepducin 脂肽，可靶向并抑制 PAR2。在监测 PAR2 刺激的细胞内 Ca2+ 浓度变化的研究中，我们表明 P2pal-18S 是腺泡细胞中的完全 PAR2 抑制剂。我们的体内研究表明，P2pal-18S 显着降低了逆行导管内胆汁酸输注诱导的实验性胆源性胰腺炎的严重程度，这模拟了内镜逆行胰胆管造影 (ERCP) 诱导的损伤。当胆汁酸输注前或输注后 2 小时给予 pepducin 时，可以观察到胰腺炎严重程度的减轻，但在胆汁酸输注后 5 小时给予 pepducin 则观察不到。相反，P2pal-18S 会增加促分泌素诱发的胰腺炎的严重程度。体外研究表明，P2pal-18S 可以保护腺泡细胞免受胆汁酸诱导的损伤/死亡，但它不会改变胆汁酸诱导的细胞内酶原激活。这些研究首次报道了有效的 PAR2 药理学抑制剂对胰腺腺泡细胞和实验性胰腺炎严重程度的影响。他们提出了一种可能性，即 P2pal-18S 等 pepducin 可能在对有严重胆源性胰腺炎风险的患者（例如 ERCP 后发生的患者）的临床管理中有用。
Michael ES, Kuliopulos A, Covic L, Steer ML, Perides G. Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis. Am J Physiol Gastrointest Liver Physiol 304: G516-G526, 2013. First published December 28, 2012; doi:10.1152/ajpgi.00296.2012.-Pancreatic acinar cells express proteinase-activated receptor-2 (PAR2) that is activated by trypsin-like serine proteases and has been shown to exert model-specific effects on the severity of experimental pancreatitis, i.e., PAR2(-/-) mice are protected from experimental acute biliary pancreatitis but develop more severe secretagogue-induced pancreatitis. P2pal-18S is a novel pepducin lipopeptide that targets and inhibits PAR2. In studies monitoring PAR2-stimulated intracellular Ca2+ concentration changes, we show that P2pal-18S is a full PAR2 inhibitor in acinar cells. Our in vivo studies show that P2pal-18S significantly reduces the severity of experimental biliary pancreatitis induced by retrograde intraductal bile acid infusion, which mimics injury induced by endoscopic retrograde cholangiopancreatography (ERCP). This reduction in pancreatitis severity is observed when the pepducin is given before or 2 h after bile acid infusion but not when it is given 5 h after bile acid infusion. Conversely, P2pal-18S increases the severity of secretagogue-induced pancreatitis. In vitro studies indicate that P2pal-18S protects acinar cells against bile acid-induced injury/death, but it does not alter bile acid-induced intracellular zymogen activation. These studies are the first to report the effects of an effective PAR2 pharmacological inhibitor on pancreatic acinar cells and on the severity of experimental pancreatitis. They raise the possibility that a pepducin such as P2pal-18S might prove useful in the clinical management of patients at risk for developing severe biliary pancreatitis such as occurs following ERCP.