Abstract：
The serine protease chymotrypsin protects the pancreas against pancreatitis by degrading trypsinogen, the precursor to the digestive protease trypsin. Taking advantage of previously generated mouse models with either the Ctrb1 gene (encoding chymotrypsin B1) or the Ctrl gene (encoding chymotrypsin-like protease) disrupted, here we generated the novel Ctrb1-del ×Ctrl-KO strain in the C57BL/6N genetic background, which harbors a naturally inactivated Ctrc gene (encoding chymotrypsin C). The newly created mice are devoid of chymotrypsin yet the animals develop normally, breed well, and show no spontaneous phenotype, indicating that chymotrypsin is dispensable under laboratory conditions. When given cerulein, the Ctrb1-del ×Ctrl-KO strain exhibited markedly increased intrapancreatic trypsin activation and more severe acute pancreatitis, relative to wild-type C57BL/6N mice. After the acute episode, Ctrb1-del ×Ctrl-KO mice spontaneously progressed to chronic pancreatitis while C57BL/6N mice recovered rapidly. The cerulein-induced pancreas pathology in Ctrb1-del ×Ctrl-KO mice was highly similar to that previously observed in Ctrb1-del mice, however, trypsin activation was more robust and pancreatitis severity was increased. Taken together, the results confirm and extend prior observations demonstrating that chymotrypsin safeguards the pancreas against pancreatitis by limiting pathologic trypsin activity. In mice, the CTRB1 isoform, which constitutes about 90% of the total chymotrypsin content, is responsible primarily for the anti-trypsin defenses and protection against pancreatitis, however, the minor isoform CTRL also contributes to an appreciable extent.
摘要：
丝氨酸蛋白酶胰凝乳蛋白酶通过降解胰蛋白酶原保护胰腺免受胰腺炎，消化蛋白酶胰蛋白酶的前体。利用先前生成的Ctrb1基因（编码胰凝乳蛋白酶B1）或Ctrl基因（编码胰凝乳蛋白酶样蛋白酶）破坏的小鼠模型，在这里，我们产生了C57BL/6N遗传背景下的新型Ctrb1-del×Ctrl-KO菌株，其具有天然失活的Ctrc基因(编码胰凝乳蛋白酶C)。新产生的小鼠缺乏胰凝乳蛋白酶，但动物发育正常，繁殖好，并且没有表现出自发的表型，表明胰凝乳蛋白酶在实验室条件下是可有可无的。当给予cerulein时，Ctrb1-del×Ctrl-KO菌株表现出显著增加的胰腺内胰蛋白酶激活和更严重的急性胰腺炎，相对于野生型C57BL/6N小鼠。急性发作后,Ctrb1-del×Ctrl-KO小鼠自发发展为慢性胰腺炎，而C57BL/6N小鼠恢复迅速。Ctrb1-del×Ctrl-KO小鼠中cerulein诱导的胰腺病理学与先前在Ctrb1-del小鼠中观察到的高度相似，然而,胰蛋白酶激活更稳健,胰腺炎严重程度增加.一起来看,结果证实并扩展了先前的观察结果，这些观察表明胰凝乳蛋白酶通过限制病理胰蛋白酶活性来保护胰腺免受胰腺炎的侵害。在老鼠身上,CTRB1亚型，约占胰凝乳蛋白酶总含量的90%，主要负责抗胰蛋白酶防御和预防胰腺炎，然而,次要同工型CTRL也有明显的贡献。
