Transgenic expression of pancreatic secretory trypsin inhibitor-1 ameliorates secretagogue-induced pancreatitis in mice
Transgenic expression of pancreatic secretory trypsin inhibitor-1 ameliorates secretagogue-induced pancreatitis in mice
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DOI：
10.1053/j.gastro.2004.11.052
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发表时间：
2005-03-01
期刊：
影响因子：
29.4
通讯作者：
Liddle, RA
中科院分区：
文献类型：
--
作者：
Nathan, JD;Romac, J;Liddle, RA
背景和目标：如果胰蛋白酶在腺泡细胞内被无意中激活，则认为内源性胰蛋白酶抑制剂抑制蛋白酶活性。然而，这一作用尚未得到证实，内源性胰蛋白酶抑制剂在急性胰腺炎中的作用尚不清楚。在这项研究中，我们测试了小鼠胰腺分泌型胰蛋白酶I（PSTI-I）水平的增加是否可以预防促分泌素诱导的胰腺炎。研究方法：通过创建由大鼠弹性蛋白酶I增强子/启动子驱动的小基因，将大鼠PSTI-I表达靶向转基因小鼠的胰腺腺泡细胞。通过每12小时腹腔注射雨蛙肽来实现促分泌素诱导的胰腺炎。胰腺炎的严重程度通过测量血清淀粉酶、组织学分级和胰腺湿重/体重比来评估。胰蛋白酶原活化和胰蛋白酶活性测定胰腺提取物。结果如下：PSTI-I在胰腺的靶向表达使转基因小鼠与非转基因小鼠的内源性胰蛋白酶抑制剂能力增加了190%（P <0.01）。非转基因小鼠注射雨蛙肽后，出现急性胰腺炎的组织学证据，血清淀粉酶和胰腺重量比显著升高。在雨蛙素处理的转基因小鼠中，胰腺炎的组织学严重程度显著降低。在雨蛙素处理的转基因和非转基因小鼠之间胰蛋白酶原激活肽水平没有差异。然而，胰蛋白酶活性显着降低转基因小鼠接受雨蛙肽相比，非转基因小鼠。结论：这些数据表明，促分泌素诱导的胰腺炎的严重程度在具有较高胰腺胰蛋白酶抑制剂水平的小鼠中显著改善。我们认为PSTI-I通过抑制胰蛋白酶的活性而不是通过减少胰蛋白酶原的激活来预防胰腺炎。
Background & Aims: Endogenous trypsin inhibitors are believed to inhibit protease activity if trypsin becomes inadvertently activated within the acinar cell. However, this action remains unproven, and the role of endogenous pancreatic trypsin inhibitors in acute pancreatitis is unknown. In this study, we tested whether increased levels of pancreatic secretory trypsin inhibitor-I (PSTI-I) in mice could prevent secretagogue-induced pancreatitis. Methods: Rat PSTI-I expression was targeted to pancreatic acinar cells in transgenic mice by creating a minigene driven by the rat elastase I enhancer/promoter. Secretagogue-induced pancreatitis was achieved by 12 hourly intraperitoneal injections of caerulein. The severity of pancreatitis was assessed by measurements of serum amylase, histologic grading, and pancreas wet weight-to-body weight ratio. Trypsinogen activation and trypsin activity were measured in pancreatic extracts. Results: Targeted expression of PSTI-I to the pancreas increased endogenous trypsin inhibitor capacity by 190% (P < .01) in transgenic vs. nontransgenic mice. Caerulein administration to nontransgenic mice produced histologic evidence of acute pancreatitis, and significantly elevated serum amylase and pancreas weight ratio. in caerulein-treated transgenic mice, the histologic severity of pancreatitis was significantly reduced. There was no difference in trypsinogen activation peptide levels between caerulein-treated transgenic and nontransgenic mice. However, trypsin activity was significantly lower in transgenic mice receiving caerulein compared with nontransgenic mice. Conclusions: These data demonstrate that the severity of secretagogue-induced pancreatitis is significantly ameliorated in mice with higher pancreatic levels of trypsin inhibitor. We propose that PSTI-I prevents pancreatitis by inhibiting the activity of trypsin, rather than by reducing trypsinogen activation.