Cerulein-induced in vitro activation of trypsinogen in rat pancreatic acini is mediated by cathepsin B
Cerulein-induced in vitro activation of trypsinogen in rat pancreatic acini is mediated by cathepsin B
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DOI：
10.1016/s0016-5085(97)70108-2
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发表时间：
1997-07-01
期刊：
影响因子：
29.4
通讯作者：
Steer, ML
中科院分区：
文献类型：
--
作者：
Saluja, AK;Donovan, EA;Steer, ML
背景与目的：急性胰腺炎发病机制中未解决的核心问题之一是消化酶原在胰腺内过早激活的机制的不确定性。当前研究的目的是开发和表征一个体外系统，该系统可以模拟胰腺炎期间导致胰腺内胰蛋白酶原激活的事件。方法：对离体大鼠胰腺腺泡中胰蛋白酶原响应雨蛙蛋白刺激的激活进行定量。结果：将分离的大鼠胰腺腺泡置于含 Ca2+ 的缓冲液中，在体外暴露于超最大刺激浓度的雨蛙蛋白后 10 分钟内即可检测到胰蛋白酶原的激活。 E-64d 是一种特异性、强效且不可逆的组织蛋白酶 B 抑制剂，可完全抑制胰腺组织蛋白酶 B 活性，从而防止雨蛙素诱导的体外胰蛋白酶原激活。结论：当胰腺腺泡暴露于超最大刺激剂量的雨蛙素时，可以在体外检测到胰蛋白酶原的激活。使用该体外系统的结果支持以下假设：在雨蛙蛋白诱导的胰腺炎的早期阶段，胰腺内出现活性胰蛋白酶反映了溶酶体水解酶组织蛋白酶 B 激活胰蛋白酶原。
Background & Aims: One of the central, unresolved issues in the pathogenesis of acute pancreatitis is the uncertainty regarding the mechanisms responsible for the premature intrapancreatic activation of digestive enzyme zymogens. The aim of the current study was to develop and characterize an in vitro system that might mimic the events leading to trypsinogen activation within the pancreas during pancreatitis. Methods: Activation of trypsinogen in response to stimulation with cerulein was quantitated in isolated rat pancreatic acini. Results: Activation of trypsinogen was detected within 10 minutes of exposing isolated rat pancreatic acini, in Ca2+-containing buffer, to a supramaximally stimulating concentration of cerulein in vitro. Complete inhibition of pancreatic cathepsin B activity with E-64d, a specific, potent and irreversible cathepsin B inhibitor, prevents cerulein-induced in vitro trypsinogen activation. Conclusions: In vitro activation of trypsinogen can be detected when pancreatic acini are exposed to a supramaximally stimulating dose of cerulein. The results using this in vitro system support the hypothesis that the appearance of active trypsin within the pancreas during the early stages of cerulein-induced pancreatitis reflects activation of trypsinogen by the lysosomal hydrolase cathepsin B.